WO2014020546A2 - Crystalline forms of dabigatran etexilate and process for their preparation - Google Patents

Crystalline forms of dabigatran etexilate and process for their preparation Download PDF

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Publication number
WO2014020546A2
WO2014020546A2 PCT/IB2013/056266 IB2013056266W WO2014020546A2 WO 2014020546 A2 WO2014020546 A2 WO 2014020546A2 IB 2013056266 W IB2013056266 W IB 2013056266W WO 2014020546 A2 WO2014020546 A2 WO 2014020546A2
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WIPO (PCT)
Prior art keywords
dabigatran etexilate
crystalline form
xrpd pattern
dabigatran
values
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PCT/IB2013/056266
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French (fr)
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WO2014020546A3 (en
Inventor
Balaguru Murugesan
Sudhir Singh Sanwal
Anandam VEMAPLI
Swargam Sathyanarayana
Rajesh Kumar Thaper
Mohan Prasad
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Ranbaxy Laboratories Limited
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Publication of WO2014020546A2 publication Critical patent/WO2014020546A2/en
Publication of WO2014020546A3 publication Critical patent/WO2014020546A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Definitions

  • the present invention relates to crystalline Form 1 , Form 2, Form 3, and Form 4 of dabigatran etexilate and processes for their preparation.
  • the present invention further relates to processes for the preparation of a dabigatran etexilate methanesulfonate salt using crystalline Form 1 , Form 2, Form 3, and Form 4 of dabigatran etexilate.
  • PRADAXA ® is the methanesulfonate salt of dabigatran etexilate, which is chemically described as ⁇ -Alanine, N-[[2-[[[4-[[[(hexyloxy)carbonyl]amino]iminomethyl] phenyl] amino]methyl]-l -methyl- lH-benzimidazol-5-yl]carbonyl]-N-2-pyridinyl-,ethyl ester, methanesulfonate salt of Formula I.
  • FORMULA II is a prodrug of dabigatran of Formula III
  • Dabigatran etexilate is indicated to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation. It may be used alone or in combination with other therapeutic agents.
  • the present invention relates to crystalline Form 1, Form 2, Form 3, and Form 4 of dabigatran etexilate and processes for their preparation.
  • the present invention further relates to processes for the preparation of dabigatran etexilate methanesulfonate salt using crystalline Form 1, Form 2, Form 3, and Form 4 of dabigatran etexilate.
  • Figure 1 depicts the X-ray powder diffraction (XRPD) pattern of crystalline Form 1 of dabigatran etexilate obtained according to Example 1.
  • Figure 1A provides the table of values for the XRPD pattern depicted in Figure 1.
  • Figure 2 depicts the XRPD pattern of crystalline Form 2 of dabigatran etexilate obtained according to Example 2.
  • Figure 2A provides the table of values for the XRPD pattern depicted in Figure 2.
  • Figure 3 depicts the XRPD pattern of crystalline Form 3 of dabigatran etexilate 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 XRPD pattern of crystalline Form 4 of dabigatran etexilate obtained according to Example 4.
  • Figure 4A provides the table of values for the XRPD pattern depicted in Figure 4.
  • Figure 5 depicts the Differential Scanning Calorimetry (DSC) thermogram of crystalline Form 1 of dabigatran etexilate obtained according to Example 1.
  • Figure 6 depicts the DSC thermogram of crystalline Form 2 of dabigatran etexilate obtained according to Example 2.
  • Figure 7 depicts the DSC thermogram of crystalline Form 3 of dabigatran etexilate obtained according to Example 3.
  • a first aspect of the present invention provides crystalline Form 1 of dabigatran etexilate.
  • the crystalline Form 1 of dabigatran etexilate has substantially the same XRPD (X-ray powder diffraction) pattern as depicted in Figure 1.
  • the crystalline Form 1 of dabigatran etexilate is characterized by an XRPD pattern having interplanar spacing (d) values substantially at 5.74, 4.42, 4.00, 3.68, 3.63, and 3.48 A.
  • the crystalline Form 1 of dabigatran etexilate is further characterized by an XRPD pattern having interplanar spacing (d) values at about 20.03, 18.28, 10.62, 10.06, 8.53, 7.68, 6.69, 6.44, 6.04, 5.74, 5.34, 5.23, 4.94, 4.42, 4.28, 4.13, 4.00, 3.92, 3.82, 3.68, 3.63, 3.48, 3.35, 3.25, 3.16, 3.1 1, 3.03, 2.87, 2.78, 2.72, 2.65, 2.59, 2.46, and 2.32 A.
  • d interplanar spacing
  • the crystalline Form 1 of dabigatran etexilate may further be characterized by a differential scanning calorimetry (DSC) thermogram substantially the same as that depicted in Figure 5.
  • the crystalline Form 1 of dabigatran etexilate has characteristic DSC endothermic peaks at about 51.42°C, 73.42°C, 99.62°C, 108.41°C, 121.91°C, and 131.52°C.
  • a second aspect of the present invention provides crystalline Form 2 of dabigatran etexilate.
  • the crystalline Form 2 of dabigatran etexilate has substantially the same XRPD pattern as depicted in Figure 2.
  • the crystalline Form 2 of dabigatran etexilate is characterized by an XRPD pattern having interplanar spacing (d) values at about 14.95, 7.48, 4.96, 4.49, 4.27, 4.16, 3.57, and 3.40 A.
  • the crystalline Form 2 of dabigatran etexilate is further characterized by an XRPD pattern having interplanar spacing (d) values at about 14.95, 13.43, 10.69, 8.04, 7.48, 7.28, 6.74, 6.45, 5.92, 5.75, 4.96, 4.49, 4.40, 4.27, 4.16, 3.84, 3.67, 3.57, 3.40, 3.32, 3.16, 2.73, and 2.49 A.
  • the crystalline Form 2 of dabigatran etexilate may further be characterized by a differential scanning calorimetry (DSC) thermogram substantially the same as that depicted in Figure 6.
  • the crystalline Form 2 of dabigatran etexilate has a characteristic DSC endothermic peak at about 77.61°C.
  • a third aspect of the present invention provides crystalline Form 3 of dabigatran etexilate.
  • the crystalline Form 3 of dabigatran etexilate has substantially the same XRPD pattern as depicted in Figure 3.
  • the crystalline Form 3 of dabigatran etexilate is characterized by an XRPD pattern having interplanar spacing (d) values at about 6.57,
  • the crystalline Form 3 of dabigatran etexilate is further characterized by an XRPD pattern having interplanar spacing (d) values at about 27.77,
  • the crystalline Form 3 of dabigatran etexilate may further be characterized by a differential scanning calorimetry (DSC) thermogram substantially the same as depicted in Figure 7.
  • the crystalline Form 3 of dabigatran etexilate has characteristic DSC endothermic peaks at about 53.67°C, 75.66°C, 106.58°C, 122.12°C, and 131.22°C.
  • a fourth aspect of the present invention provides crystalline Form 4 of dabigatran etexilate.
  • the crystalline Form 4 of dabigatran etexilate has substantially the same XRPD pattern as depicted in Figure 4.
  • the crystalline Form 4 of dabigatran etexilate is characterized by an XRPD pattern having interplanar spacing (d) values at about 10.00, 5.71, 5.33, 4.41, 3.68, and 3.62 A.
  • the crystalline Form 4 of dabigatran etexilate is further characterized by an XRPD pattern having interplanar spacing (d) values at about 18.05, 10.45, 10.00, 8.53, 7.61, 6.70, 6.50, 6.34, 6.03, 5.71, 5.33, 5.09, 4.88, 4.41, 4.27, 4.13, 4.01, 3.91 , 3.81, 3.68, 3.62, 3.54, 3.48, 3.34, 3.25, 3.17, 3.12, 3.02, 2.85, 2.78, 2.72, 2.66, 2.58, 2.46, and 2.32 A.
  • a fifth aspect of the present invention provides a process for the preparation of crystalline Form 1 of dabigatran etexilate wherein the process comprises:
  • Dabigatran etexilate existing in any solid or non-solid form known in the prior art may be used as the starting material.
  • Dabigatran etexilate may be prepared, for example, according to the methods disclosed in U.S. Patent No. 6,087,380.
  • Dabigatran etexilate is treated with hexanol.
  • the treatment with hexanol may be carried out at a temperature of about 10°C to about 100°C, for example, about 20°C to about 80°C.
  • the treatment with hexanol may be carried out for about 2 hours to about 7 hours, for example, about 4 hours to about 5 hours.
  • the hexanol may be used alone or in combination with an organic solvent.
  • the treatment with hexanol is optionally preceded or followed by treatment with an organic solvent.
  • the organic solvent may be selected from the group comprising of alcohols, esters, nitriles, or mixtures thereof.
  • the alcohol may be, for example, ethanol, methanol, 2-propanol, or butanol.
  • the ester may be, for example, methyl acetate, ethyl acetate, or butyl acetate.
  • the nitrile may be, for example, acetonitrile.
  • the reaction mixture is stirred for about 1 hour to about 5 hours, for example, about 2 hours to about 3 hours.
  • the crystalline Form 1 of dabigatran etexilate may be isolated from the reaction mixture by filtration, cooling, evaporation, decantation, distillation, vacuum drying, or combinations thereof.
  • a sixth aspect of the present invention provides a process for the preparation of crystalline Form 2 of dabigatran etexilate, wherein the process comprises:
  • Dabigatran etexilate existing in any solid or non-solid form known in the prior art may be used as the starting material.
  • Dabigatran etexilate may be prepared, for example, according to the methods disclosed in U.S. Patent No. 6,087,380.
  • Dabigatran etexilate is treated with t-butanol at a temperature of about 10°C to about 100°C, for example, about 20°C to about 80°C.
  • the treatment with t-butanol may be carried out for about 2 hours to about 7 hours, for example about 4 hours to about 5 hours.
  • the t-butanol may be used alone, or in combination with an organic solvent.
  • the treatment with t-butanol is optionally preceded or followed by treatment with an organic solvent.
  • the organic solvent may be selected from the group comprising of alcohols, esters, nitriles, or mixtures thereof.
  • the alcohol may be, for example, ethanol, methanol, 2-propanol, or butanol.
  • the ester may be, for example, methyl acetate, ethyl acetate, or butyl acetate.
  • the nitrile may be, for example, acetonitrile.
  • the reaction mixture is stirred for about 1 hour to about 5 hours, for example, about 2 hours to about 3 hours.
  • the crystalline Form 2 of dabigatran etexilate may be isolated from the reaction mixture by filtration, cooling, evaporation, decantation, distillation, vacuum drying, or combinations thereof.
  • a seventh aspect of the present invention provides a process for the preparation of crystalline Form 3 of dabigatran etexilate wherein the process comprises:
  • Dabigatran etexilate existing in any solid or non-solid form known in the prior art may be used as the starting material.
  • Dabigatran etexilate may be prepared, for example, according to the methods disclosed in U.S. Patent No. 6,087,380.
  • Dabigatran etexilate is treated with toluene at a temperature of about 10°C to about 100°C, for example, about 20°C to about 80°C, for about 2 hours to about 7 hours, for example, about 4 hours to about 5 hours.
  • the toluene may be used alone, or in combination with an organic solvent.
  • the treatment with toluene is optionally preceded or followed by treatment with an organic solvent.
  • the organic solvent may be selected from the group comprising of alcohols, esters, nitriles, or mixtures thereof.
  • the alcohol may be, for example, ethanol, methanol, 2-propanol, or butanol.
  • the ester may be, for example, methyl acetate, ethyl acetate, or butyl acetate.
  • the nitrile may be, for example, acetonitrile.
  • the reaction mixture is stirred for about 1 hour to about 5 hours, for example, about 2 hours to about 3 hours.
  • the crystalline Form 3 of dabigatran etexilate may be isolated from the reaction mixture by filtration, cooling, evaporation, decantation, distillation, vacuum drying, or combinations thereof.
  • An eighth aspect of the present invention provides a process for the preparation of crystalline Form 4 of dabigatran etexilate wherein the process comprises:
  • Dabigatran etexilate existing in any solid or non-solid form known in the prior art may be used as the starting material.
  • Dabigatran etexilate may be prepared, for example, according to the methods disclosed in U.S. Patent No. 6,087,380.
  • Dabigatran etexilate is treated with methyl acetate.
  • the treatment with methyl acetate may be carried out at a temperature of about 10°C to about 100°C, for example, about 20°C to about 80°C.
  • the treatment with methyl acetate may be carried out for about 2 hours to about 7 hours, for example, about 4 hours to about 5 hours.
  • the methyl acetate may be used alone or in combination with an organic solvent.
  • the treatment with methyl acetate is optionally preceded or followed by treatment with an organic solvent.
  • the organic solvent may be selected from the group comprising of alcohols, esters, nitriles, or mixtures thereof.
  • the alcohol may be, for example, ethanol, methanol, 2-propanol, or butanol.
  • the ester may be, for example, ethyl acetate, or butyl acetate.
  • the nitrile may be, for example, acetonitrile.
  • the reaction mixture is stirred for about 1 hour to about 5 hours, for example, about 2 hours to about 3 hours.
  • the crystalline Form 4 of dabigatran etexilate may be isolated from the reaction mixture by filtration, cooling, evaporation, decantation, distillation, vacuum drying, or combinations thereof.
  • a ninth aspect of the present invention provides a process for the preparation of dabigatran etexilate methanesulfonate salt wherein the process comprises:
  • a tenth aspect of the present invention provides a pharmaceutical composition comprising crystalline Form 1, Form 2, Form 3, or Form 4 of dabigatran etexilate, or any combination of said forms, and a pharmaceutically acceptable excipient.
  • An eleventh aspect of the present invention provides a method of treating or preventing blood clots in a patient suffering from or susceptible to the formation of blood clots, comprising administering a pharmaceutical composition comprising crystalline Form 1, Form 2, Form 3, or Form 4 of dabigatran etexilate, or any combination of said forms.
  • Dabigatran etexilate (2 g) was added to hexanol (25 mL) at 25°C to 30°C.
  • the temperature of the reaction mixture was increased to 70°C to 75°C, and the mixture was stirred for 5 minutes to 10 minutes.
  • the reaction mixture was cooled to 20°C to 25°C and stirred for 2 hours to 3 hours.
  • the solid obtained was filtered under vacuum, and washed with hexanol (10 mL). The solid obtained was suck dried, and further dried under vacuum at 50°C to 55°C for 15 hours to give the title compound having an XRPD pattern as shown in Figure 1.
  • Dabigatran etexilate (2 g) was added to t-butanol (25 mL) at 25°C to 30°C.
  • the temperature of the reaction mixture was increased to 70°C to 75°C, and it was stirred for 5 minutes to 10 minutes.
  • the reaction mixture was cooled to 20°C to 25°C and stirred for 2 hours to 3 hours.
  • the solid obtained was filtered under vacuum and washed with t-butanol (10 mL). The solid obtained was suck dried, and further dried under vacuum at 50°C to 55°C for 15 hours to give the title compound having an XRPD pattern as shown in Figure 2.
  • Dabigatran etexilate (2 g) was added to toluene (25 mL) at 25°C to 30°C.
  • the temperature of the reaction mixture was increased to 70°C to 75°C, and it was stirred for 5 minutes to 10 minutes.
  • the reaction mixture was cooled to 20°C to 25°C and stirred for 2 hours to 3 hours.
  • the solid obtained was filtered under vacuum and washed with toluene (10 mL). The solid obtained was suck dried, and further dried under vacuum at 50°C to 55°C for 15 hours to give the title compound having an XRPD pattern as shown in Figure 3.
  • Dabigatran etexilate (2 g) was added to methyl acetate (25 mL) at 25°C to 30°C.
  • the temperature of the reaction mixture was increased to 70°C to 75°C, and it was stirred for 5 minutes to 10 minutes.
  • the reaction mixture was cooled to 20°C to 25°C, and stirred for 2 hours to 3 hours.
  • the solid obtained was filtered under vacuum and washed with methyl acetate (10 mL). The solid obtained was suck dried, and further dried under vacuum at 50°C to 55°C for 15 hours to give the title compound having XRPD as shown in Figure 4.

Abstract

The present invention relates to crystalline Form 1, Form 2, Form 3, and Form 4 of dabigatran etexilate, and processes for their preparation. The present invention further relates to processes for the preparation of a dabigatran etexilate methanesulfonate salt using crystalline Form 1, Form 2, Form 3, and Form 4 of dabigatran etexilate.

Description

CRYSTALLINE FORMS OF DABIGATRAN ETEXILATE AND PROCESS FOR
THEIR PREPARATION
Field of the Invention
The present invention relates to crystalline Form 1 , Form 2, Form 3, and Form 4 of dabigatran etexilate and processes for their preparation. The present invention further relates to processes for the preparation of a dabigatran etexilate methanesulfonate salt using crystalline Form 1 , Form 2, Form 3, and Form 4 of dabigatran etexilate.
Background of the Invention
The drug substance used in the commercial drug product formulation of
PRADAXA® is the methanesulfonate salt of dabigatran etexilate, which is chemically described as β-Alanine, N-[[2-[[[4-[[[(hexyloxy)carbonyl]amino]iminomethyl] phenyl] amino]methyl]-l -methyl- lH-benzimidazol-5-yl]carbonyl]-N-2-pyridinyl-,ethyl ester, methanesulfonate salt of Formula I.
Figure imgf000002_0001
FORMULA I
Dabigatran etexilate of Formula II
Figure imgf000002_0002
FORMULA II is a prodrug of dabigatran of Formula III
Figure imgf000003_0001
FORMULA III
which is a direct thrombin inhibitor. Dabigatran etexilate is indicated to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation. It may be used alone or in combination with other therapeutic agents.
Processes for the preparation of dabigatran etexilate and its methanesulfonate salt are described in U.S. Patent No. 6,087,380; U.S. Patent Application Nos. 2006/0183779, 2006/0276513, and PCT Publication Nos. WO 2012/027543, WO 2008/059029, WO 201 1/1 10478.
Summary of the Invention
The present invention relates to crystalline Form 1, Form 2, Form 3, and Form 4 of dabigatran etexilate and processes for their preparation. The present invention further relates to processes for the preparation of dabigatran etexilate methanesulfonate salt using crystalline Form 1, Form 2, Form 3, and Form 4 of dabigatran etexilate.
Brief Description of the Drawings
Figure 1 depicts the X-ray powder diffraction (XRPD) pattern of crystalline Form 1 of dabigatran etexilate obtained according to Example 1.
Figure 1A provides the table of values for the XRPD pattern depicted in Figure 1. Figure 2 depicts the XRPD pattern of crystalline Form 2 of dabigatran etexilate obtained according to Example 2.
Figure 2A provides the table of values for the XRPD pattern depicted in Figure 2.
Figure 3 depicts the XRPD pattern of crystalline Form 3 of dabigatran etexilate 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 XRPD pattern of crystalline Form 4 of dabigatran etexilate obtained according to Example 4.
Figure 4A provides the table of values for the XRPD pattern depicted in Figure 4.
Figure 5 depicts the Differential Scanning Calorimetry (DSC) thermogram of crystalline Form 1 of dabigatran etexilate obtained according to Example 1.
Figure 6 depicts the DSC thermogram of crystalline Form 2 of dabigatran etexilate obtained according to Example 2.
Figure 7 depicts the DSC thermogram of crystalline Form 3 of dabigatran etexilate obtained according to Example 3.
Detailed Description of the Invention
A first aspect of the present invention provides crystalline Form 1 of dabigatran etexilate.
The crystalline Form 1 of dabigatran etexilate has substantially the same XRPD (X-ray powder diffraction) pattern as depicted in Figure 1. The crystalline Form 1 of dabigatran etexilate is characterized by an XRPD pattern having interplanar spacing (d) values substantially at 5.74, 4.42, 4.00, 3.68, 3.63, and 3.48 A. The crystalline Form 1 of dabigatran etexilate is further characterized by an XRPD pattern having interplanar spacing (d) values at about 20.03, 18.28, 10.62, 10.06, 8.53, 7.68, 6.69, 6.44, 6.04, 5.74, 5.34, 5.23, 4.94, 4.42, 4.28, 4.13, 4.00, 3.92, 3.82, 3.68, 3.63, 3.48, 3.35, 3.25, 3.16, 3.1 1, 3.03, 2.87, 2.78, 2.72, 2.65, 2.59, 2.46, and 2.32 A.
The crystalline Form 1 of dabigatran etexilate may further be characterized by a differential scanning calorimetry (DSC) thermogram substantially the same as that depicted in Figure 5. The crystalline Form 1 of dabigatran etexilate has characteristic DSC endothermic peaks at about 51.42°C, 73.42°C, 99.62°C, 108.41°C, 121.91°C, and 131.52°C.
A second aspect of the present invention provides crystalline Form 2 of dabigatran etexilate.
The crystalline Form 2 of dabigatran etexilate has substantially the same XRPD pattern as depicted in Figure 2. The crystalline Form 2 of dabigatran etexilate is characterized by an XRPD pattern having interplanar spacing (d) values at about 14.95, 7.48, 4.96, 4.49, 4.27, 4.16, 3.57, and 3.40 A. The crystalline Form 2 of dabigatran etexilate is further characterized by an XRPD pattern having interplanar spacing (d) values at about 14.95, 13.43, 10.69, 8.04, 7.48, 7.28, 6.74, 6.45, 5.92, 5.75, 4.96, 4.49, 4.40, 4.27, 4.16, 3.84, 3.67, 3.57, 3.40, 3.32, 3.16, 2.73, and 2.49 A.
The crystalline Form 2 of dabigatran etexilate may further be characterized by a differential scanning calorimetry (DSC) thermogram substantially the same as that depicted in Figure 6. The crystalline Form 2 of dabigatran etexilate has a characteristic DSC endothermic peak at about 77.61°C.
A third aspect of the present invention provides crystalline Form 3 of dabigatran etexilate.
The crystalline Form 3 of dabigatran etexilate has substantially the same XRPD pattern as depicted in Figure 3. The crystalline Form 3 of dabigatran etexilate is characterized by an XRPD pattern having interplanar spacing (d) values at about 6.57,
5.71, 4.00, 3.93, 3.62, and 3.47 A. The crystalline Form 3 of dabigatran etexilate is further characterized by an XRPD pattern having interplanar spacing (d) values at about 27.77,
19.61, 18.13, 10.59, 10.01, 9.07, 8.51, 7.64, 6.57, 6.43, 6.04, 5.71, 5.32, 5.13, 4.92, 4.47, 4.41, 4.27, 4.12, 4.00, 3.93, 3.82, 3.62, 3.47, 3.33, 3.25, 3.17, 3.10, 3.01, 2.97, 2.86, 2.77,
2.72, 2.58, 2.46, and 2.31 A.
The crystalline Form 3 of dabigatran etexilate may further be characterized by a differential scanning calorimetry (DSC) thermogram substantially the same as depicted in Figure 7. The crystalline Form 3 of dabigatran etexilate has characteristic DSC endothermic peaks at about 53.67°C, 75.66°C, 106.58°C, 122.12°C, and 131.22°C.
A fourth aspect of the present invention provides crystalline Form 4 of dabigatran etexilate.
The crystalline Form 4 of dabigatran etexilate has substantially the same XRPD pattern as depicted in Figure 4. The crystalline Form 4 of dabigatran etexilate is characterized by an XRPD pattern having interplanar spacing (d) values at about 10.00, 5.71, 5.33, 4.41, 3.68, and 3.62 A. The crystalline Form 4 of dabigatran etexilate is further characterized by an XRPD pattern having interplanar spacing (d) values at about 18.05, 10.45, 10.00, 8.53, 7.61, 6.70, 6.50, 6.34, 6.03, 5.71, 5.33, 5.09, 4.88, 4.41, 4.27, 4.13, 4.01, 3.91 , 3.81, 3.68, 3.62, 3.54, 3.48, 3.34, 3.25, 3.17, 3.12, 3.02, 2.85, 2.78, 2.72, 2.66, 2.58, 2.46, and 2.32 A. A fifth aspect of the present invention provides a process for the preparation of crystalline Form 1 of dabigatran etexilate wherein the process comprises:
a) treating dabigatran etexilate with hexanol; and
b) isolating Form 1 of dabigatran etexilate from the mixture thereof.
Dabigatran etexilate existing in any solid or non-solid form known in the prior art may be used as the starting material. Dabigatran etexilate may be prepared, for example, according to the methods disclosed in U.S. Patent No. 6,087,380. Dabigatran etexilate is treated with hexanol. The treatment with hexanol may be carried out at a temperature of about 10°C to about 100°C, for example, about 20°C to about 80°C. The treatment with hexanol may be carried out for about 2 hours to about 7 hours, for example, about 4 hours to about 5 hours. The hexanol may be used alone or in combination with an organic solvent. The treatment with hexanol is optionally preceded or followed by treatment with an organic solvent. The organic solvent may be selected from the group comprising of alcohols, esters, nitriles, or mixtures thereof. The alcohol may be, for example, ethanol, methanol, 2-propanol, or butanol. The ester may be, for example, methyl acetate, ethyl acetate, or butyl acetate. The nitrile may be, for example, acetonitrile. The reaction mixture is stirred for about 1 hour to about 5 hours, for example, about 2 hours to about 3 hours. The crystalline Form 1 of dabigatran etexilate may be isolated from the reaction mixture by filtration, cooling, evaporation, decantation, distillation, vacuum drying, or combinations thereof.
A sixth aspect of the present invention provides a process for the preparation of crystalline Form 2 of dabigatran etexilate, wherein the process comprises:
a) treating dabigatran etexilate with t-butanol; and
b) isolating Form 2 of dabigatran etexilate from the mixture thereof.
Dabigatran etexilate existing in any solid or non-solid form known in the prior art may be used as the starting material. Dabigatran etexilate may be prepared, for example, according to the methods disclosed in U.S. Patent No. 6,087,380. Dabigatran etexilate is treated with t-butanol at a temperature of about 10°C to about 100°C, for example, about 20°C to about 80°C. The treatment with t-butanol may be carried out for about 2 hours to about 7 hours, for example about 4 hours to about 5 hours. The t-butanol may be used alone, or in combination with an organic solvent. The treatment with t-butanol is optionally preceded or followed by treatment with an organic solvent. The organic solvent may be selected from the group comprising of alcohols, esters, nitriles, or mixtures thereof. The alcohol may be, for example, ethanol, methanol, 2-propanol, or butanol. The ester may be, for example, methyl acetate, ethyl acetate, or butyl acetate. The nitrile may be, for example, acetonitrile. The reaction mixture is stirred for about 1 hour to about 5 hours, for example, about 2 hours to about 3 hours. The crystalline Form 2 of dabigatran etexilate may be isolated from the reaction mixture by filtration, cooling, evaporation, decantation, distillation, vacuum drying, or combinations thereof.
A seventh aspect of the present invention provides a process for the preparation of crystalline Form 3 of dabigatran etexilate wherein the process comprises:
a) treating dabigatran etexilate with toluene; and
b) isolating Form 3 of dabigatran etexilate from the mixture thereof.
Dabigatran etexilate existing in any solid or non-solid form known in the prior art may be used as the starting material. Dabigatran etexilate may be prepared, for example, according to the methods disclosed in U.S. Patent No. 6,087,380. Dabigatran etexilate is treated with toluene at a temperature of about 10°C to about 100°C, for example, about 20°C to about 80°C, for about 2 hours to about 7 hours, for example, about 4 hours to about 5 hours. The toluene may be used alone, or in combination with an organic solvent. The treatment with toluene is optionally preceded or followed by treatment with an organic solvent. The organic solvent may be selected from the group comprising of alcohols, esters, nitriles, or mixtures thereof. The alcohol may be, for example, ethanol, methanol, 2-propanol, or butanol. The ester may be, for example, methyl acetate, ethyl acetate, or butyl acetate. The nitrile may be, for example, acetonitrile. The reaction mixture is stirred for about 1 hour to about 5 hours, for example, about 2 hours to about 3 hours. The crystalline Form 3 of dabigatran etexilate may be isolated from the reaction mixture by filtration, cooling, evaporation, decantation, distillation, vacuum drying, or combinations thereof.
An eighth aspect of the present invention provides a process for the preparation of crystalline Form 4 of dabigatran etexilate wherein the process comprises:
a) treating dabigatran etexilate with methyl acetate; and
b) isolating Form 4 of dabigatran etexilate from the mixture thereof. Dabigatran etexilate existing in any solid or non-solid form known in the prior art may be used as the starting material. Dabigatran etexilate may be prepared, for example, according to the methods disclosed in U.S. Patent No. 6,087,380. Dabigatran etexilate is treated with methyl acetate. The treatment with methyl acetate may be carried out at a temperature of about 10°C to about 100°C, for example, about 20°C to about 80°C. The treatment with methyl acetate may be carried out for about 2 hours to about 7 hours, for example, about 4 hours to about 5 hours. The methyl acetate may be used alone or in combination with an organic solvent. The treatment with methyl acetate is optionally preceded or followed by treatment with an organic solvent. The organic solvent may be selected from the group comprising of alcohols, esters, nitriles, or mixtures thereof. The alcohol may be, for example, ethanol, methanol, 2-propanol, or butanol. The ester may be, for example, ethyl acetate, or butyl acetate. The nitrile may be, for example, acetonitrile. The reaction mixture is stirred for about 1 hour to about 5 hours, for example, about 2 hours to about 3 hours. The crystalline Form 4 of dabigatran etexilate may be isolated from the reaction mixture by filtration, cooling, evaporation, decantation, distillation, vacuum drying, or combinations thereof.
A ninth aspect of the present invention provides a process for the preparation of dabigatran etexilate methanesulfonate salt wherein the process comprises:
a) treating crystalline Form 1, Form 2, Form 3, or Form 4 of dabigatran etexilate with methane sulfonic acid; and
b) isolating dabigatran etexilate methanesulfonate salt from the mixture thereof.
A tenth aspect of the present invention provides a pharmaceutical composition comprising crystalline Form 1, Form 2, Form 3, or Form 4 of dabigatran etexilate, or any combination of said forms, and a pharmaceutically acceptable excipient.
An eleventh aspect of the present invention provides a method of treating or preventing blood clots in a patient suffering from or susceptible to the formation of blood clots, comprising administering a pharmaceutical composition comprising crystalline Form 1, Form 2, Form 3, or Form 4 of dabigatran etexilate, or any combination of said forms.
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 Form 1 of Dabigatran Etexilate
Dabigatran etexilate (2 g) was added to hexanol (25 mL) at 25°C to 30°C. The temperature of the reaction mixture was increased to 70°C to 75°C, and the mixture was stirred for 5 minutes to 10 minutes. The reaction mixture was cooled to 20°C to 25°C and stirred for 2 hours to 3 hours. The solid obtained was filtered under vacuum, and washed with hexanol (10 mL). The solid obtained was suck dried, and further dried under vacuum at 50°C to 55°C for 15 hours to give the title compound having an XRPD pattern as shown in Figure 1.
Yield: 60%
Example 2: Preparation of Crystalline Form 2 of Dabigatran Etexilate
Dabigatran etexilate (2 g) was added to t-butanol (25 mL) at 25°C to 30°C. The temperature of the reaction mixture was increased to 70°C to 75°C, and it was stirred for 5 minutes to 10 minutes. The reaction mixture was cooled to 20°C to 25°C and stirred for 2 hours to 3 hours. The solid obtained was filtered under vacuum and washed with t-butanol (10 mL). The solid obtained was suck dried, and further dried under vacuum at 50°C to 55°C for 15 hours to give the title compound having an XRPD pattern as shown in Figure 2.
Yield: 67.5%
Example 3 : Preparation of Crystalline Form 3 of Dabigatran Etexilate
Dabigatran etexilate (2 g) was added to toluene (25 mL) at 25°C to 30°C. The temperature of the reaction mixture was increased to 70°C to 75°C, and it was stirred for 5 minutes to 10 minutes. The reaction mixture was cooled to 20°C to 25°C and stirred for 2 hours to 3 hours. The solid obtained was filtered under vacuum and washed with toluene (10 mL). The solid obtained was suck dried, and further dried under vacuum at 50°C to 55°C for 15 hours to give the title compound having an XRPD pattern as shown in Figure 3.
Yield: 85% Example 4: Preparation of Crystalline Form 4 of Dabigatran Etexilate
Dabigatran etexilate (2 g) was added to methyl acetate (25 mL) at 25°C to 30°C. The temperature of the reaction mixture was increased to 70°C to 75°C, and it was stirred for 5 minutes to 10 minutes. The reaction mixture was cooled to 20°C to 25°C, and stirred for 2 hours to 3 hours. The solid obtained was filtered under vacuum and washed with methyl acetate (10 mL). The solid obtained was suck dried, and further dried under vacuum at 50°C to 55°C for 15 hours to give the title compound having XRPD as shown in Figure 4.
Yield: 70%

Claims

We claim:
1. Crystalline Form 1 of dabigatran etexilate having substantially the same XRPD (X- ray powder diffraction) pattern as depicted in Figure 1.
2. Crystalline Form 1 of dabigatran etexilate characterized by an XRPD pattern having interplanar spacing (d) values at about 5.74, 4.42, 4.00, 3.68, 3.63, and 3.48 A. 3. The crystalline Form 1 of dabigatran etexilate according to claim 2, further characterized by an XRPD pattern having interplanar spacing (d) values at about 20.03, 18.28, 10.62, 10.06, 8.53, 7.68, 6.69, 6.44, 6.04, 5.74, 5.34, 5.23, 4.94, 4.42, 4.28, 4.13, 4.00, 3.92, 3.82, 3.68, 3.63, 3.48, 3.35, 3.25, 3.16, 3.1 1,
3.03, 2.87, 2.78, 2.72, 2.65, 2.59, 2.46, and 2.32 A.
4. Crystalline Form 1 of dabigatran etexilate having substantially the same differential scanning calorimetry (DSC) thermogram as depicted in Figure 5.
5. The crystalline Form 1 of dabigatran etexilate according to claim 4, further characterized by DSC endothermic peaks at about 51.42°C, 73.42°C, 99.62°C, 108.41°C, 121.91°C, and l31.52°C.
6. Crystalline Form 2 of dabigatran etexilate substantially having the same XRPD pattern as depicted in Figure 2.
7. Crystalline Form 2 of dabigatran etexilate characterized by an XRPD pattern having interplanar spacing (d) values at about 14.95, 7.48, 4.96, 4.49, 4.27, 4.16, 3.57, and 3.40 A.
8. The crystalline Form 2 of dabigatran etexilate according to claim 7, further characterized by an XRPD pattern having interplanar spacing (d) values at about 14.95, 13.43, 10.69, 8.04, 7.48, 7.28, 6.74, 6.45, 5.92, 5.75, 4.96, 4.49, 4.40, 4.27, 4.16, 3.84, 3.67, 3.57, 3.40, 3.32, 3.16, 2.73, and 2.49 A.
9. Crystalline Form 2 of dabigatran etexilate having substantially the same differential scanning calorimetry (DSC) thermogram as depicted in Figure 6.
10. The crystalline Form 2 of dabigatran etexilate according to claim 9, further characterized by a DSC endothermic peak at about 77.61°C.
11. Crystalline Form 3 of dabigatran etexilate having substantially the same XRPD pattern as depicted in Figure 3.
12. Crystalline Form 3 of dabigatran etexilate characterized by an XRPD pattern having interplanar spacing (d) values at about 6.57, 5.71, 4.00, 3.93, 3.62, and 3.47 A.
13. The crystalline Form 3 of dabigatran etexilate according to claim 12, further characterized by an XRPD pattern having interplanar spacing (d) values at about 27.77, 19.61, 18.13, 10.59, 10.01, 9.07, 8.51, 7.64, 6.57, 6.43, 6.04, 5.71, 5.32, 5.13, 4.92, 4.47, 4.41, 4.27, 4.12, 4.00, 3.93, 3.82, 3.62, 3.47, 3.33, 3.25, 3.17, 3.10, 3.01, 2.97, 2.86, 2.77, 2.72, 2.58, 2.46, and 2.31 A.
14. Crystalline Form 3 of dabigatran etexilate having substantially the same differential scanning calorimetry (DSC) thermogram as depicted in Figure 7.
15. The crystalline Form 3 of dabigatran etexilate according to claim 14, further characterized by DSC endothermic peaks at about 53.67°C, 75.66°C, 106.58°C, 122.12°C, and l31.22°C.
16. Crystalline Form 4 of dabigatran etexilate having substantially the same XRPD pattern as depicted in Figure 4.
17. Crystalline Form 4 of dabigatran etexilate characterized by an XRPD pattern having interplanar spacing (d) values at about 10.00, 5.71, 5.33, 4.41, 3.68, and 3.62 A.
18. The crystalline Form 4 of dabigatran etexilate according to claim 17, further characterized by an XRPD pattern having interplanar spacing (d) values at about 18.05, 10.45, 10.00, 8.53, 7.61, 6.70, 6.50, 6.34, 6.03, 5.71, 5.33, 5.09, 4.88, 4.41, 4.27, 4.13, 4.01, 3.91, 3.81, 3.68, 3.62, 3.54, 3.48, 3.34, 3.25, 3.17, 3.12, 3.02, 2.85, 2.78, 2.72, 2.66, 2.58, 2.46, and 2.32 A.
19. A process for the preparation of crystalline Form 1 of dabigatran etexilate wherein the process comprises:
a) treating dabigatran etexilate with hexanol; and
b) isolating Form 1 of dabigatran etexilate from the mixture thereof.
20. A process for the preparation of crystalline Form 2 of dabigatran etexilate, wherein the process comprises:
a) treating dabigatran etexilate with t-butanol; and
b) isolating Form 2 of dabigatran etexilate from the mixture thereof.
21. A process for the preparation of crystalline Form 3 of dabigatran etexilate wherein the process comprises:
a) treating dabigatran etexilate with toluene; and
b) isolating Form 3 of dabigatran etexilate from the mixture thereof.
22. A process for the preparation of crystalline Form 4 of dabigatran etexilate wherein the process comprises:
a) treating dabigatran etexilate with methyl acetate; and
b) isolating Form 4 of dabigatran etexilate from the mixture thereof.
23. A process for the preparation of dabigatran etexilate methanesulfonate salt wherein the process comprises:
a) treating crystalline Form 1, Form 2, Form 3, or Form 4 of dabigatran etexilate with methane sulfonic acid; and
b) isolating dabigatran etexilate methanesulfonate salt from the mixture thereof.
24. A pharmaceutical composition comprising crystalline Form 1, Form 2, Form 3, or Form 4 of dabigatran etexilate, or combinations thereof, and a pharmaceutically acceptable excipient.
25. A method of treating or preventing blood clots in a patient suffering from or susceptible to the formation of blood clots, comprising administering a pharmaceutical composition comprising crystalline Form 1, Form 2, Form 3, or Form 4 of dabigatran etexilate, or combinations thereof.
PCT/IB2013/056266 2012-07-31 2013-07-30 Crystalline forms of dabigatran etexilate and process for their preparation WO2014020546A2 (en)

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