WO2014178017A1 - Dabigatran etexilate impurity, process of its preparation, and its use as a reference standard - Google Patents

Dabigatran etexilate impurity, process of its preparation, and its use as a reference standard Download PDF

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Publication number
WO2014178017A1
WO2014178017A1 PCT/IB2014/061119 IB2014061119W WO2014178017A1 WO 2014178017 A1 WO2014178017 A1 WO 2014178017A1 IB 2014061119 W IB2014061119 W IB 2014061119W WO 2014178017 A1 WO2014178017 A1 WO 2014178017A1
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formula
dabigatran etexilate
amino pyridine
impurity
salts
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PCT/IB2014/061119
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French (fr)
Inventor
Pratibha Singh
Seshi Reddy SURASANI
Kaushal Nayyar
Jagdev Singh Jaryal
Sudhir Singh Sanwal
Swargam Sathyanarayana
Rajesh Kumar Thaper
Mohan Prasad
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Ranbaxy Laboratories Limited
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Publication of WO2014178017A1 publication Critical patent/WO2014178017A1/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
    • C07D401/14—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 three or more hetero rings
    • 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

Definitions

  • the present invention relates to an isolated amino pyridine impurity of dabigatran etexilate, processes for its preparation, and its use as a reference standard in a chromatographic method for testing the purity of dabigatran etexilate mesylate salt active pharmaceutical ingredient or dosage form.
  • Dabigatran etexilate mesylate is chemically designated as ⁇ -Alanine, N-[[2-[[[4- [ [ [(hexy loxy)carbony 1] amino] iminomethyljphenyl] amino]methyl] - 1 -methyl- 1 H- benzimidazol-5-yl]carbonyl]-N-2-pyridinyl-,ethyl ester methane sulfonate. Its chemical structure is depicted below in Formula I:
  • Dabigatran etexilate mesylate salt is marketed as Pradaxa ® and 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 an isolated amino pyridine impurity of dabigatran etexilate, processes for its preparation, and its use as a reference standard for testing the purity of dabigatran etexilate mesylate salt active pharmaceutical ingredient (API) or dosage form (DF).
  • API active pharmaceutical ingredient
  • DF dosage form
  • a first aspect of the present invention provides an isolated amino pyridine impurity of Formula V.
  • a second aspect of the present invention provides a process for the preparation of the amino pyridine impurity of Formula V
  • a third aspect of the present invention provides the use of the amino pyridine impurity of Formula V as a reference standard for analyzing the purity of a sample comprising dabigatran etexilate.
  • a fourth aspect of the present invention provides the use of the amino pyridine impurity of Formula V as a reference standard for analyzing the purity of a sample comprising dabigatran etexilate, salts, or solvates thereof, as the active pharmaceutical ingredient.
  • a fifth aspect of the present invention provides the use of the amino pyridine impurity of Formula V as a reference standard for analyzing the purity of a pharmaceutical composition comprising dabigatran etexilate, salts, or solvates thereof.
  • a sixth aspect of the present invention provides a chromatographic method for testing the purity of a sample comprising dabigatran etexilate, salts, or solvates thereof by determining the presence of the amino pyridine impurity of Formula V in the sample, comprising the steps of:
  • a seventh aspect of the present invention provides a process for preparing dabigatran etexilate, salts, or solvates thereof suitable for pharmaceutical use, comprising the steps of:
  • step c) assessing the purity of dabigatran etexilate, salts, or solvates thereof by using the amino pyridine impurity of Formula V as a reference standard; and c) subjecting the dabigatran etexilate, salts, or solvates thereof to purification wherein step c) may be carried out before or after step b).
  • An eighth aspect of the present invention provides dabigatran etexilate or
  • Figure 1 is a High-Performance Liquid Chromatogram (HPLC) of a standard solution of the amino pyridine impurity of dabigatran etexilate.
  • Figure 2 is a HPLC of a sample of dabigatran etexilate mesylate active pharmaceutical ingredient containing the amino pyridine impurity of dabigatran etexilate.
  • substantially free of the amino pyridine impurity of Formula V includes dabigatran etexilate, salts, or solvates thereof having less than 1%, preferably less than 0.5%, and still more preferably, less than 0.1% of the amino pyridine impurity of Formula V.
  • substantially free of the amino pyridine impurity of Formula V may also include dabigatran etexilate, salts, or solvates thereof having no detectable amount of the amino pyridine impurity of Formula V.
  • reference standard refers to the amino pyridine impurity of Formula V to be used for the qualitative or quantitative analysis of a sample comprising dabigatran etexilate, salts, or solvates thereof.
  • the reference standard may be used for identifying the different components of a mixture based on the difference in their retention time in a chromatographic method, such as in an HPLC chromatogram, Liquid Chromatography-Mass Spectrometry (LC-MS) chromatogram, or on a Thin Layer
  • comparing the retention time means comparing the retention time of one of the different components of a sample of dabigatran etexilate or its salts which has been separated by a chromatographic technique with the retention time of amino pyridine impurity of Formula V under the same chromatographic conditions
  • substantially the same in relation to comparing the retention time, as used herein, means that the difference in retention times is less than 10%, preferably less than 5%, more preferably less than 1%, still more preferably less than 0.5%, or most preferably less than 0.1%.
  • a first aspect of the present invention provides an isolated amino pyridine impurity of Formula V.
  • the amino pyridine impurity of Formula V is chemically designated as hexyl [(Z)- amino(4- ⁇ [( 1 -methyl-5- ⁇ [3 -oxo-3 -(pyridin-2-ylamino)propyl] (pyridin-2-yl)carbamoyl ⁇ - lH-benzimidazol-2-yl)methyl]amino ⁇ phenyl)methylidene]carbamate.
  • a second aspect of the present invention provides a process for the preparation of the amino pyridine impurity of Formula V
  • the preparation of the amino pyridine impurity of Formula V is carried out by reacting 2-amino pyridine with ethyl magnesium bromide before its reaction with dabigatran etexilate of Formula II.
  • the reaction of 2-amino pyridine with dabigatran etexilate of Formula II may be carried out in the presence of a solvent selected from the group consisting of ethers, alcohols, amides, halogenated hydrocarbons, esters, or mixtures thereof.
  • ethers include tetrahydrofuran, diisopropyl ether, methyl t-butyl ether, or mixtures thereof.
  • Examples of alcohols include methanol, ethanol, 2-propanol, 1-propanol, butanol, or mixtures thereof.
  • Examples of amides include N-methylpyrrolidone, dimethyl acetamide, dimethyl formamide, or mixtures thereof.
  • Examples of halogenated hydrocarbons include dichloromethane, chloroform, or mixtures thereof.
  • Examples of esters include ethyl acetate, methyl acetate, isopropyl acetate, or mixtures thereof.
  • the solvent used is tetrahydrofuran.
  • a solution of ammonium chloride is added to the reaction mixture containing 2-amino pyridine and dabigatran etexilate of Formula II.
  • the reaction of 2-amino pyridine with dabigatran etexilate of Formula II is carried out at a temperature of about -10°C to about 70°C. In a preferred embodiment of the present invention, the reaction is carried out at a temperature of about 0°C to about 50°C.
  • the reaction of 2-amino pyridine with dabigatran etexilate of Formula II is carried out for about 1 hour to about 6 hours. In a preferred embodiment of the present invention, the reaction is carried out for about 2 hours to about 4 hours.
  • the amino pyridine impurity of Formula V may be further purified by using column chromatography using solvents selected from the group consisting of halogenated hydrocarbons, esters, ethers, alcohols, amides, or mixtures thereof as eluents.
  • halogenated hydrocarbons include dichloromethane, chloroform, or mixtures thereof.
  • esters include ethyl acetate, methyl acetate, isopropyl acetate, or mixtures thereof.
  • ethers include tetrahydrofuran, diisopropyl ether, methyl t-butyl ether, or mixtures thereof.
  • alcohols include methanol, ethanol, 2-propanol, 1- propanol, butanol, or mixtures thereof.
  • amides include N-methylpyrrolidone, dimethyl acetamide, dimethyl formamide, or mixtures thereof.
  • dichloromethane, ethyl acetate, ethanol, or mixtures thereof are used as eluents.
  • the purification of the amino pyridine impurity of Formula V is carried out at a temperature of about 10°C to about 70°C. In a preferred embodiment of the present invention, the purification is carried out at a temperature of about 20°C to about 50°C.
  • V is carried out over a period of about 1 hour to about 6 hours.
  • the purification may be carried out over a period of about 2 hours to about 4 hours.
  • the isolation of the amino pyridine impurity of Formula V may be carried out by filtration, distillation, decantation, vacuum drying, evaporation, or combinations thereof.
  • a third aspect of the present invention provides the use of the amino pyridine impurity of Formula V as a reference standard for analyzing the purity of a sample comprising dabigatran etexilate.
  • a fourth aspect of the present invention provides the use of the amino pyridine impurity of Formula V as a reference standard for analyzing the purity of a sample comprising dabigatran etexilate, salts, or solvates thereof as the active pharmaceutical ingredient.
  • a fifth aspect of the present invention provides the use of the amino pyridine impurity of Formula V as a reference standard for analyzing the purity of a pharmaceutical composition comprising dabigatran etexilate, salts, or solvates thereof.
  • a sixth aspect of the present invention provides a chromatographic method for testing the purity of a sample comprising dabigatran etexilate, salts, or solvates thereof by determining the presence of the amino pyridine impurity of Formula V in the sample comprising the steps of:
  • the reference standard solution comprises a solution of the amino pyridine impurity of Formula V in a solvent, such as acetonitrile.
  • the presence of the amino pyridine impurity of Formula V in a sample of dabigatran etexilate, salts, or solvates thereof may be determined by chromatographic techniques such as HPLC, LC-MS, or TLC by comparing the retention time of different components of a sample of dabigatran etexilate, salts, or solvates thereof with the retention time of the amino pyridine impurity of Formula V.
  • a seventh aspect of the present invention provides a process for preparing dabigatran etexilate, salts, or solvates thereof suitable for pharmaceutical use comprising the steps of:
  • step c) assessing the purity of dabigatran etexilate, salts, or solvates thereof by using the amino pyridine impurity of Formula V as a reference standard; and c) subjecting the dabigatran etexilate, salts, or solvates thereof to purification wherein step c) may be carried out before or after step b).
  • the reference standard solution comprises a solution of the amino pyridine impurity of Formula V in a solvent, such as acetonitrile.
  • Assessing the purity of dabigatran etexilate, salts, or solvates thereof (such as dabigatran etexilate mesylate or a solvate thereof) using the amino pyridine impurity of Formula V as a reference standard refers to determining the concentration of amino pyridine impurity of Formula V in a sample comprising dabigatran etexilate, salts, or solvates thereof.
  • concentration of the amino pyridine impurity of dabigatran etexilate of Formula V is determined by conventional methods known in the art, such as by HPLC or LC-MS.
  • dabigatran etexilate, salts, or solvates thereof may be carried out using purification techniques known to the skilled in the art, such as chromatography, distillation, and crystallization.
  • the present invention provides the use of the amino pyridine impurity of Formula V as a reference standard to quantify the amount of the amino pyridine impurity of Formula V in a sample of dabigatran etexilate, salts, or solvates thereof.
  • An eighth aspect of the present invention provides dabigatran etexilate or dabigatran etexilate mesylate salt substantially free of the amino pyridine impurity of Formula V.
  • the IR spectrum was recorded using a PerkinElmer ® Spectrum One FT-IR spectrometer.
  • the mass spectrum was recorded using an API 2000 LCMS/MS system.
  • the NMR spectrum was recorded using a Bruker ® Avance III 400 MHz instrument.
  • HPLC purity was determined using a Kromasil ® C18, (250 mm x 4.6 mm), 3.5 ⁇ column with a flow rate 0.8 mL/minute -1.2 mL/minute; Column oven temperature: 35°C; Sample tray temperature: 10°C; Detector: UV at 300 nm; Injection volume: 10 ⁇ ; Run time: 65 minutes.
  • Example 1 Preparation of hexyl r(Z)-amino(4- (l-methyl-5- 3-oxo-3-(pyridin-2- ylamino)propyll(pyridin-2-yl)carbamoyl ⁇ -lH-benzimidazol-2-yl)methyllamino ⁇ phenyl) methylidenelcarbamate (amino pyridine impurity of Formula V)
  • the organic layer (50 mL) was separated and concentrated under reduced pressure to obtain the crude amino pyridine impurity (5.0 g).
  • the crude amino pyridine impurity was purified using column chromatography, by passing it through a column packed with neutral alumina using methanol (16 mL) in dichloromethane (800 mL) as the eluent to obtain a second crop of the crude amino pyridine impurity (2.5 g).
  • Ethyl acetate (15 mL) was added to the second crop of the crude amino pyridine impurity at 40°C to 50°C, the contents were cooled to 25°C to 30°C, and ethanol (1 mL) was added. The contents were stirred at 25 °C to 30°C for 1 hour, filtered, and dried to obtain the amino pyridine impurity of Formula V.
  • Example 2 HPLC method for the analysis of hexyl r(Z)-amino(4- ⁇ r(l-methyl-5- ⁇ r3-oxo-
  • the chromatographic separation was carried out in a Kromasil ® C18, 3.5 ⁇ , 250 x 4.6 mm column at a temperature of 35°C, using a UV detector at a wavelength of 300 nm.
  • the buffer solution was prepared by dissolving ammonium acetate (1.54 g) in water (1000 mL), and filtering the solution through a 0.45 micron filter or through a finer porosity membrane filter.
  • the mobile phase/diluent was prepared by mixing a suitable quantity of a degassed mixture of acetonitrile and buffer (1 mL of orthophosphoric acid in 1000 mL of water) in the ratio 20:80 (v/v).
  • the analysis of the amino pyridine impurity of Formula V in a sample of dabigatran etexilate mesylate was carried out by injecting 10 of the test sample (prepared by dissolving 25 mg of dabigatran etexilate in 5 mL of diluents, and making up the volume to 25 mL by adding the diluent followed by filtration through a 0.45 ⁇ nylon filter) into the column, and running the chromatogram for 65 minutes.
  • the retention time for dabigatran etexilate mesylate was observed to be about 42.4 minutes, and the retention time for amino pyridine impurity of Formula V was observed to be 36.7 minutes.
  • Figure 1 provides the HPLC chromatogram of a standard solution of the amino pyridine impurity of dabigatran etexilate.
  • Figure 2 provides the HPLC chromatogram of a sample of dabigatran etexilate mesylate active pharmaceutical ingredient containing the amino pyridine impurity of dabigatran etexilate.

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Abstract

The present invention relates to an isolated amino pyridine impurity (V) of dabigatran etexilate (II). Also disclosed are processes for their preparation, the use of the said impurity as a reference standard in a chromatographic method for testing the purity of dabigatran etexilate mesylate salt active pharmaceutical ingredient or dosage form.

Description

DABIGATRAN ETEXILATE IMPURITY, PROCESS OF ITS PREPARATION, AND ITS USE AS A REFERENCE STANDARD
Field of the Invention
The present invention relates to an isolated amino pyridine impurity of dabigatran etexilate, processes for its preparation, and its use as a reference standard in a chromatographic method for testing the purity of dabigatran etexilate mesylate salt active pharmaceutical ingredient or dosage form.
Background of the Invention
Dabigatran etexilate mesylate is chemically designated as β-Alanine, N-[[2-[[[4- [ [ [(hexy loxy)carbony 1] amino] iminomethyljphenyl] amino]methyl] - 1 -methyl- 1 H- benzimidazol-5-yl]carbonyl]-N-2-pyridinyl-,ethyl ester methane sulfonate. Its chemical structure is depicted below in Formula I:
Figure imgf000002_0001
FORMULA I
Dabigatran etexilate of Formula II:
Figure imgf000002_0002
FORMULA II
etexilate prodrug of dabigatran ethyl ester of Formula III,
Figure imgf000003_0001
FORMULA III
which in turn is a prodrug of dabigatran of Formula IV, a direct thrombin inhibitor.
Figure imgf000003_0002
FORMULA IV
Dabigatran etexilate mesylate salt is marketed as Pradaxa® and 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 or its salts are described in U.S. Patent No. 6,087,380; U.S. Publication No. U.S. 2006/0183779; and PCT Publication Nos. WO 2006/114415 (US 2006/247278), WO 2008/043759, WO 2012/044595, WO 2012/027543, WO 2008/059029, WO 2011/110876, WO 2011/110478, and WO
2006/131491 (US 2006/276513).
Summary of the Invention
The present invention relates to an isolated amino pyridine impurity of dabigatran etexilate, processes for its preparation, and its use as a reference standard for testing the purity of dabigatran etexilate mesylate salt active pharmaceutical ingredient (API) or dosage form (DF).
A first aspect of the present invention provides an isolated amino pyridine impurity of Formula V.
Figure imgf000004_0001
FORMULA V
A second aspect of the present invention provides a process for the preparation of the amino pyridine impurity of Formula V
Figure imgf000004_0002
FORMULA V
comprising the steps of:
a) reacting dabigatran etexilate of Formula II
Figure imgf000004_0003
FORMULA II
with 2-amino pyridine; and b) isolating the amino pyridine impurity of Formula V.
A third aspect of the present invention provides the use of the amino pyridine impurity of Formula V as a reference standard for analyzing the purity of a sample comprising dabigatran etexilate.
A fourth aspect of the present invention provides the use of the amino pyridine impurity of Formula V as a reference standard for analyzing the purity of a sample comprising dabigatran etexilate, salts, or solvates thereof, as the active pharmaceutical ingredient.
A fifth aspect of the present invention provides the use of the amino pyridine impurity of Formula V as a reference standard for analyzing the purity of a pharmaceutical composition comprising dabigatran etexilate, salts, or solvates thereof.
A sixth aspect of the present invention provides a chromatographic method for testing the purity of a sample comprising dabigatran etexilate, salts, or solvates thereof by determining the presence of the amino pyridine impurity of Formula V in the sample, comprising the steps of:
a) dissolving dabigatran etexilate, salts, or solvates thereof in a solvent to obtain a sample solution;
b) dissolving a sample of the amino pyridine impurity of Formula V in a solvent to prepare a reference standard solution;
c) subjecting the sample solution and the reference standard solution to a
chromatographic technique; and
d) determining the presence of the amino pyridine impurity of Formula V in the sample of dabigatran etexilate, salts, or solvates thereof using the reference standard solution.
A seventh aspect of the present invention provides a process for preparing dabigatran etexilate, salts, or solvates thereof suitable for pharmaceutical use, comprising the steps of:
a) preparing dabigatran etexilate, salts, or solvates thereof;
b) assessing the purity of dabigatran etexilate, salts, or solvates thereof by using the amino pyridine impurity of Formula V as a reference standard; and c) subjecting the dabigatran etexilate, salts, or solvates thereof to purification wherein step c) may be carried out before or after step b).
An eighth aspect of the present invention provides dabigatran etexilate or
dabigatran etexilate mesylate substantially free of the amino pyridine impurity of Formula V.
Brief Description of the Drawings
Figure 1 is a High-Performance Liquid Chromatogram (HPLC) of a standard solution of the amino pyridine impurity of dabigatran etexilate.
Figure 2 is a HPLC of a sample of dabigatran etexilate mesylate active pharmaceutical ingredient containing the amino pyridine impurity of dabigatran etexilate.
Detailed Description of the Invention
Various aspects and embodiments of the present invention are described hereafter.
The term "about", as used herein, refers to any value which lies within the range defined by a variation of ±10% of the value.
The term "substantially free of the amino pyridine impurity of Formula V", as used herein, includes dabigatran etexilate, salts, or solvates thereof having less than 1%, preferably less than 0.5%, and still more preferably, less than 0.1% of the amino pyridine impurity of Formula V. The term "substantially free of the amino pyridine impurity of Formula V" may also include dabigatran etexilate, salts, or solvates thereof having no detectable amount of the amino pyridine impurity of Formula V.
The term "reference standard", as used herein, refers to the amino pyridine impurity of Formula V to be used for the qualitative or quantitative analysis of a sample comprising dabigatran etexilate, salts, or solvates thereof. The reference standard may be used for identifying the different components of a mixture based on the difference in their retention time in a chromatographic method, such as in an HPLC chromatogram, Liquid Chromatography-Mass Spectrometry (LC-MS) chromatogram, or on a Thin Layer
Chromatography (TLC) plate.
In the context of the present invention, the phrase "comparing the retention time" means comparing the retention time of one of the different components of a sample of dabigatran etexilate or its salts which has been separated by a chromatographic technique with the retention time of amino pyridine impurity of Formula V under the same chromatographic conditions, The phrase "substantially the same", in relation to comparing the retention time, as used herein, means that the difference in retention times is less than 10%, preferably less than 5%, more preferably less than 1%, still more preferably less than 0.5%, or most preferably less than 0.1%.
A first aspect of the present invention provides an isolated amino pyridine impurity of Formula V.
Figure imgf000007_0001
FORMULA V
The amino pyridine impurity of Formula V is chemically designated as hexyl [(Z)- amino(4- { [( 1 -methyl-5- { [3 -oxo-3 -(pyridin-2-ylamino)propyl] (pyridin-2-yl)carbamoyl } - lH-benzimidazol-2-yl)methyl]amino}phenyl)methylidene]carbamate.
A second aspect of the present invention provides a process for the preparation of the amino pyridine impurity of Formula V
Figure imgf000007_0002
FORMULA V
comprising the steps of:
a) reacting dabigatran etexilate of Formula II
Figure imgf000008_0001
FORMULA II
with 2-amino pyridine; and
b) isolating the amino pyridine impurity of Formula V.
In an embodiment of this aspect of the present invention, the preparation of the amino pyridine impurity of Formula V is carried out by reacting 2-amino pyridine with ethyl magnesium bromide before its reaction with dabigatran etexilate of Formula II. The reaction of 2-amino pyridine with dabigatran etexilate of Formula II may be carried out in the presence of a solvent selected from the group consisting of ethers, alcohols, amides, halogenated hydrocarbons, esters, or mixtures thereof. Examples of ethers include tetrahydrofuran, diisopropyl ether, methyl t-butyl ether, or mixtures thereof. Examples of alcohols include methanol, ethanol, 2-propanol, 1-propanol, butanol, or mixtures thereof. Examples of amides include N-methylpyrrolidone, dimethyl acetamide, dimethyl formamide, or mixtures thereof. Examples of halogenated hydrocarbons include dichloromethane, chloroform, or mixtures thereof. Examples of esters include ethyl acetate, methyl acetate, isopropyl acetate, or mixtures thereof. In a preferred embodiment of the present invention, the solvent used is tetrahydrofuran. A solution of ammonium chloride is added to the reaction mixture containing 2-amino pyridine and dabigatran etexilate of Formula II.
The reaction of 2-amino pyridine with dabigatran etexilate of Formula II is carried out at a temperature of about -10°C to about 70°C. In a preferred embodiment of the present invention, the reaction is carried out at a temperature of about 0°C to about 50°C.
The reaction of 2-amino pyridine with dabigatran etexilate of Formula II is carried out for about 1 hour to about 6 hours. In a preferred embodiment of the present invention, the reaction is carried out for about 2 hours to about 4 hours. The amino pyridine impurity of Formula V may be further purified by using column chromatography using solvents selected from the group consisting of halogenated hydrocarbons, esters, ethers, alcohols, amides, or mixtures thereof as eluents. Examples of halogenated hydrocarbons include dichloromethane, chloroform, or mixtures thereof. Examples of esters include ethyl acetate, methyl acetate, isopropyl acetate, or mixtures thereof. Examples of ethers include tetrahydrofuran, diisopropyl ether, methyl t-butyl ether, or mixtures thereof. Examples of alcohols include methanol, ethanol, 2-propanol, 1- propanol, butanol, or mixtures thereof. Examples of amides include N-methylpyrrolidone, dimethyl acetamide, dimethyl formamide, or mixtures thereof. In the preferred embodiments of the present invention, dichloromethane, ethyl acetate, ethanol, or mixtures thereof are used as eluents.
The purification of the amino pyridine impurity of Formula V is carried out at a temperature of about 10°C to about 70°C. In a preferred embodiment of the present invention, the purification is carried out at a temperature of about 20°C to about 50°C.
The purification of the amino pyridine impurity of dabigatran etexilate of Formula
V is carried out over a period of about 1 hour to about 6 hours. In a preferred embodiment of the present invention, the purification may be carried out over a period of about 2 hours to about 4 hours.
The isolation of the amino pyridine impurity of Formula V may be carried out by filtration, distillation, decantation, vacuum drying, evaporation, or combinations thereof.
A third aspect of the present invention provides the use of the amino pyridine impurity of Formula V as a reference standard for analyzing the purity of a sample comprising dabigatran etexilate.
A fourth aspect of the present invention provides the use of the amino pyridine impurity of Formula V as a reference standard for analyzing the purity of a sample comprising dabigatran etexilate, salts, or solvates thereof as the active pharmaceutical ingredient.
A fifth aspect of the present invention provides the use of the amino pyridine impurity of Formula V as a reference standard for analyzing the purity of a pharmaceutical composition comprising dabigatran etexilate, salts, or solvates thereof.
A sixth aspect of the present invention provides a chromatographic method for testing the purity of a sample comprising dabigatran etexilate, salts, or solvates thereof by determining the presence of the amino pyridine impurity of Formula V in the sample comprising the steps of:
a) dissolving dabigatran etexilate, salts, or solvates thereof in a solvent to obtain a sample solution;
b) dissolving a sample of the amino pyridine impurity of Formula V in a solvent to make a reference standard solution;
c) subjecting the sample solution and the reference standard solution to a
chromatographic technique; and
d) determining the presence of the amino pyridine impurity of Formula V in the sample of dabigatran etexilate, salts, or solvates thereof using the reference standard solution.
The reference standard solution comprises a solution of the amino pyridine impurity of Formula V in a solvent, such as acetonitrile.
The presence of the amino pyridine impurity of Formula V in a sample of dabigatran etexilate, salts, or solvates thereof may be determined by chromatographic techniques such as HPLC, LC-MS, or TLC by comparing the retention time of different components of a sample of dabigatran etexilate, salts, or solvates thereof with the retention time of the amino pyridine impurity of Formula V.
A seventh aspect of the present invention provides a process for preparing dabigatran etexilate, salts, or solvates thereof suitable for pharmaceutical use comprising the steps of:
a) preparing dabigatran etexilate, salts, or solvates thereof;
b) assessing the purity of dabigatran etexilate, salts, or solvates thereof by using the amino pyridine impurity of Formula V as a reference standard; and c) subjecting the dabigatran etexilate, salts, or solvates thereof to purification wherein step c) may be carried out before or after step b).
The reference standard solution comprises a solution of the amino pyridine impurity of Formula V in a solvent, such as acetonitrile.
Assessing the purity of dabigatran etexilate, salts, or solvates thereof (such as dabigatran etexilate mesylate or a solvate thereof) using the amino pyridine impurity of Formula V as a reference standard refers to determining the concentration of amino pyridine impurity of Formula V in a sample comprising dabigatran etexilate, salts, or solvates thereof. Preferably, the concentration of the amino pyridine impurity of dabigatran etexilate of Formula V is determined by conventional methods known in the art, such as by HPLC or LC-MS.
The purification of dabigatran etexilate, salts, or solvates thereof may be carried out using purification techniques known to the skilled in the art, such as chromatography, distillation, and crystallization.
In a specific embodiment, the present invention provides the use of the amino pyridine impurity of Formula V as a reference standard to quantify the amount of the amino pyridine impurity of Formula V in a sample of dabigatran etexilate, salts, or solvates thereof.
An eighth aspect of the present invention provides dabigatran etexilate or dabigatran etexilate mesylate salt substantially free of the amino pyridine impurity of Formula V.
Methods
The IR spectrum was recorded using a PerkinElmer® Spectrum One FT-IR spectrometer.
The mass spectrum was recorded using an API 2000 LCMS/MS system.
The NMR spectrum was recorded using a Bruker® Avance III 400 MHz instrument.
HPLC purity was determined using a Kromasil® C18, (250 mm x 4.6 mm), 3.5 μ column with a flow rate 0.8 mL/minute -1.2 mL/minute; Column oven temperature: 35°C; Sample tray temperature: 10°C; Detector: UV at 300 nm; Injection volume: 10 μί; Run time: 65 minutes.
While the present invention has been described in terms of its specific
embodiments, certain modifications and equivalents may 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 hexyl r(Z)-amino(4- (l-methyl-5- 3-oxo-3-(pyridin-2- ylamino)propyll(pyridin-2-yl)carbamoyl}-lH-benzimidazol-2-yl)methyllamino}phenyl) methylidenelcarbamate (amino pyridine impurity of Formula V)
2 -Amino pyridine (4.42 g) was added to tetrahydrofuran (10 mL) at 0°C. A solution of ethyl magnesium bromide (2.11 g) in tetrahydrofuran (15 mL) was added to the reaction mixture at 0°C to 5°C, and the reaction mixture was stirred at 25°C to 30°C for 1 hour. A solution of dabigatran etexilate (5 g) in tetrahydrofuran (40 mL) was added to the reaction mass at 25°C to 30°C, and the reaction mixture was stirred for 1 hour. The reaction mixture was treated with a saturated ammonium chloride solution (50 mL). The organic layer (50 mL) was separated and concentrated under reduced pressure to obtain the crude amino pyridine impurity (5.0 g). The crude amino pyridine impurity was purified using column chromatography, by passing it through a column packed with neutral alumina using methanol (16 mL) in dichloromethane (800 mL) as the eluent to obtain a second crop of the crude amino pyridine impurity (2.5 g). Ethyl acetate (15 mL) was added to the second crop of the crude amino pyridine impurity at 40°C to 50°C, the contents were cooled to 25°C to 30°C, and ethanol (1 mL) was added. The contents were stirred at 25 °C to 30°C for 1 hour, filtered, and dried to obtain the amino pyridine impurity of Formula V.
Yield: 15.0%
¾ NMR (400 MHz, CDC13), δ (in ppm): 0.86 (t, 3H), 1.28 (m, 6H), 1.58 (m, 2H), 2.82 (t, 2H), 3.76 (s, 3H), 3.97 (t, 2H), 4.27 (t, 2H), 4.59 (d, 2H), 6.76 (d, 2H), 6.97 (m, 2H), 6.97 (m, 2H), 7.07 (m, 2H), 7.17 (d, 1H), 7.39 (d, 1H), 7.48 (s, 1H), 7.53 (t, 1H), 7.73 (t, 1H), 7.79 (d, 2H), 7.97 (d, 1H), 8.31 (m, 2H), 8.58 and 9.21 (2xbr, 2H), 10.51 (s, 1H).
Mass: 676.2 [M+H]+; MS/MS: 225.2, 273.1, 289.1, 332.0, 383.1, 434.3, 528.2, and 574.1.
IR, in KBr, (in cm"1): 3407 (N-H stretching), 2933, 2854 (C-H stretchings), 1707 (-C=0 stretching), 1611 (N-H deformation), 842, 786 (aryl C-H bendings). Example 2: HPLC method for the analysis of hexyl r(Z)-amino(4-{ r(l-methyl-5-{ r3-oxo-
3-(pyridin-2-ylamino)propyll(pyridin-2-yl)carbamoyl}-lH-benzimidazol-2- vDmethyll amino} phenyl) methylidenel carbamate (amino pyridine impurity of Formula V)
The chromatographic separation was carried out in a Kromasil® C18, 3.5 μιη, 250 x 4.6 mm column at a temperature of 35°C, using a UV detector at a wavelength of 300 nm.
The buffer solution was prepared by dissolving ammonium acetate (1.54 g) in water (1000 mL), and filtering the solution through a 0.45 micron filter or through a finer porosity membrane filter.
The mobile phase/diluent was prepared by mixing a suitable quantity of a degassed mixture of acetonitrile and buffer (1 mL of orthophosphoric acid in 1000 mL of water) in the ratio 20:80 (v/v).
The analysis of the amino pyridine impurity of Formula V in a sample of dabigatran etexilate mesylate was carried out by injecting 10 of the test sample (prepared by dissolving 25 mg of dabigatran etexilate in 5 mL of diluents, and making up the volume to 25 mL by adding the diluent followed by filtration through a 0.45 μ nylon filter) into the column, and running the chromatogram for 65 minutes. The retention time for dabigatran etexilate mesylate was observed to be about 42.4 minutes, and the retention time for amino pyridine impurity of Formula V was observed to be 36.7 minutes.
Figure 1 provides the HPLC chromatogram of a standard solution of the amino pyridine impurity of dabigatran etexilate.
Figure 2 provides the HPLC chromatogram of a sample of dabigatran etexilate mesylate active pharmaceutical ingredient containing the amino pyridine impurity of dabigatran etexilate.

Claims

We Claim:
1. An isolated amino pyridine impurity of Formula V.
Figure imgf000014_0001
FORMULA V
A process for the preparation of the amino pyridine impurity of Formula V
Figure imgf000014_0002
FORMULA V
comprising:
a) reacting dabigatran etexilate of Formula II
Figure imgf000014_0003
FORMULA II with 2-amino pyridine; and
b) isolating the amino pyridine impurity of Formula V.
3. The process according to claim 2, wherein 2-amino pyrimidine is reacted with ethyl magnesium bromide before reacting with dabigatran etexilate of Formula II.
4. The process according to claim 2, wherein the reaction of 2-amino pyrimidine with dabigatran etexilate of Formula II is carried out in the presence of a solvent selected from the group consisting of ethers, alcohols, amides, halogenated hydrocarbons, esters, or mixtures thereof.
5. The process according to claim 4, wherein the ether is selected from the group consisting of tetrahydrofuran, diisopropyl ether, methyl t-butyl ether, or mixtures thereof. 6 The process according to claim 4, wherein the alcohol is selected from the group consisting of methanol, ethanol, 2-propanol, 1-propanol, butanol, or mixtures thereof. 7. The process according to claim 4, wherein the amide is selected from the group consisting of N-methylpyrrolidone, dimethyl acetamide, dimethyl formamide, or mixtures thereof.
8. The process according to claim 4, wherein the halogenated hydrocarbon is selected from the group consisting of dichloromethane, chloroform, or mixtures thereof.
9. The process according to claim 4, wherein the ester is selected from the group consisting of ethyl acetate, methyl acetate, isopropyl acetate, or mixtures thereof.
10. The process according to claim 4, wherein the solvent is tetrahydrofuran.
11. The process according to claim 2, wherein a solution of ammonium chloride is added to the reaction mixture containing 2-amino pyridine and dabigatran etexilate of Formula II.
12. Use of the amino pyridine impurity of Formula V as a reference standard for analyzing the purity of a sample comprising dabigatran etexilate.
13. Use of the amino pyridine impurity of Formula V as a reference standard for analyzing the purity of a sample comprising dabigatran etexilate, salts, or solvates thereof as the active pharmaceutical ingredient.
14. Use of the amino pyridine impurity of Formula V as a reference standard for analyzing the purity of a pharmaceutical composition comprising dabigatran etexilate, salts, or solvates thereof.
15. A chromatographic method for testing the purity of a sample comprising dabigatran etexilate, salts, or solvates thereof by determining the presence of the amino pyridine impurity of Formula V in the sample comprising the steps of:
a) dissolving dabigatran etexilate, salts, or solvates thereof in a solvent to obtain a sample solution;
b) dissolving a sample of the amino pyridine impurity of Formula V in a solvent to make a reference standard solution;
c) subjecting the sample solution and the reference standard solution to a
chromatographic technique; and
d) determining the presence of the amino pyridine impurity of Formula V in the sample of dabigatran etexilate, salts, or solvates thereof using the reference standard solution.
16. The process according to claim 15, wherein the reference standard solution comprises a solution of the amino pyridine impurity of Formula V in acetonitrile.
17. A process for preparing dabigatran etexilate, salts, or solvates thereof suitable for pharmaceutical use comprising the steps of:
a) preparing dabigatran etexilate, salts, or solvates thereof;
b) assessing the purity of dabigatran etexilate, salts, or solvates thereof by using the amino pyridine impurity of Formula V as a reference standard; and c) subjecting the dabigatran etexilate, salts, or solvates thereof to purification wherein step c) may be carried out before or after step b).
18. Dabigatran etexilate or dabigatran etexilate mesylate substantially free of the amino pyridine impurity of Formula V.
PCT/IB2014/061119 2013-04-30 2014-04-30 Dabigatran etexilate impurity, process of its preparation, and its use as a reference standard WO2014178017A1 (en)

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CN114113346B (en) * 2020-08-25 2024-01-12 石药集团恩必普药业有限公司 Detection method of ethyl p-toluenesulfonate and isopropyl p-toluenesulfonate in dabigatran etexilate bulk drug or preparation

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