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WO2014178013A1 - Vilazodone impurities, process for their preparation, and their use as reference standards - Google Patents

Vilazodone impurities, process for their preparation, and their use as reference standards Download PDF

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Publication number
WO2014178013A1
WO2014178013A1 PCT/IB2014/061113 IB2014061113W WO2014178013A1 WO 2014178013 A1 WO2014178013 A1 WO 2014178013A1 IB 2014061113 W IB2014061113 W IB 2014061113W WO 2014178013 A1 WO2014178013 A1 WO 2014178013A1
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Prior art keywords
vilazodone
formula
impurity
oxo
process according
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French (fr)
Inventor
Pratibha Singh
Kaushal Nayyar
Bindu Srivastava
Sandeep TOMAR
Rajesh Kumar Thaper
Mohan Prasad
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Ranbaxy Laboratories Ltd
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Ranbaxy Laboratories Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • VILAZODONE IMPURITIES PROCESS FOR THEIR PREPARATION, AND THEIR USE AS REFERENCE STANDARDS
  • the present invention relates to isolated vilazodone N-oxide and oxo vilazodone impurities, processes for their preparation, and their use as reference standards in a chromatographic method for testing the purity of a vilazodone active pharmaceutical ingredient or dosage form.
  • Vilazodone hydrochloride is marketed in the United States under the brand name Viibryd ® and is indicated for the treatment of major depressive disorder (MDD).
  • MDD major depressive disorder
  • the present invention relates to isolated vilazodone N-oxide and oxo vilazodone impurities, processes for their preparation, and their use as reference standards in a chromatographic method for testing the purity of a vilazodone active pharmaceutical ingredient or dosage form.
  • a first aspect of the present invention provides an isolated vilazodone N-oxide impurity of Formula II.
  • a second aspect of the present invention provides an isolated oxo vilazodone im urity of Formula III.
  • a third aspect of the present invention provides a process for the preparation of the vilazodone N-oxide impurity of Formula II
  • a fourth aspect of the present invention provides a process for the preparation of oxo vilazodone im urity of Formula III
  • a fifth aspect of the present invention provides the use of the vilazodone N-oxide impurity of Formula II or the oxo vilazodone impurity of Formula III as a reference standard for analyzing the purity of vilazodone, salts, or solvates thereof.
  • a sixth aspect of the present invention provides the use of the vilazodone N-oxide impurity of Formula II or the oxo vilazodone impurity of Formula III as a reference standard for analyzing the purity of a pharmaceutical composition comprising vilazodone, salts, or solvates thereof.
  • a seventh aspect of the present invention provides a chromatographic method for testing the purity of a sample comprising vilazodone, salts, or solvates thereof by determining the presence of the vilazodone N-oxide impurity of Formula II, or the oxo vilazodone impurity of Formula III, comprising the steps of:
  • An eighth aspect of the present invention provides a method for preparing vilazodone, salts, or solvates thereof suitable for pharmaceutical use, comprising the steps of:
  • step c) subjecting the vilazodone, salts, or solvates thereof to purification wherein step c) may be carried out before or after step b).
  • a ninth aspect of the present invention provides vilazodone free base or its hydrochloride salt substantially free of the vilazodone N-oxide impurity of Formula II or the oxo vilazodone impurity of Formula III.
  • Figure 1 High-Performance Liquid Chromatogram (HPLC) of a standard solution of the vilazodone N-oxide impurity of Formula II.
  • Figure 2 HPLC of a standard solution of the oxo vilazodone impurity of Formula III.
  • Figure 3 HPLC of a sample of vilazodone active pharmaceutical ingredient containing the vilazodone N-oxide impurity of Formula II and the oxo vilazodone impurity of Formula III.
  • substantially free of the vilazodone N-oxide impurity of Formula II or the oxo vilazodone impurity of Formula III refers to vilazodone, salts, or solvates thereof having less than 1%, preferably less than 0.5%, and the most preferably less than 0.1%, of the vilazodone N-oxide impurity of Formula II or the oxo vilazodone impurity of Formula III.
  • substantially free of the vilazodone N-oxide impurity of Formula II or the oxo vilazodone impurity of Formula III may also include vilazodone, salts, or solvates thereof having no detectable amount of the vilazodone N-oxide impurity of Formula II or the oxo vilazodone impurity of Formula III.
  • reference standard refers to the vilazodone N-oxide impurity of Formula II or the oxo vilazodone impurity of Formula III to be used for the qualitative or quantitative analysis of a sample comprising vilazodone, 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.
  • comparing the retention time means comparing the retention time of one of the different components of a sample of vilazodone, salts, or solvates thereof which has been separated by a chromatographic technique with the retention time of the vilazodone N-oxide impurity of Formula II or the oxo vilazodone impurity of Formula III 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%, and the most preferably less than 0.1%.
  • a first aspect of the present invention provides an isolated vilazodone N-oxide impurity of Formula II.
  • a second aspect of the present invention provides an isolated oxo vilazodone impurity of Formula III.
  • a third aspect of the present invention provides a process for the preparation of the vilazodone N-oxide impurity of Formula II
  • the oxidizing agent may be selected from the group consisting of m-chloroperoxybenzoic acid, hydrogen peroxide, periodic acid, or ozonide.
  • m-chloroperoxybenzoic acid is used as the oxidizing agent.
  • the oxidation of vilazodone of Formula IV may be carried out in the presence of a solvent selected from the group consisting of ketones, alcohols, halogenated hydrocarbons, or mixtures thereof.
  • ketones include acetone, methyl butyl ketone, methyl isobutyl ketone, or mixtures thereof.
  • alcohols include methanol, ethanol, 2- propanol, or mixtures thereof.
  • halogenated hydrocarbons include dichloromethane, chloroform, or mixtures thereof. In a preferred embodiment of the present invention, methanol and acetone are used as solvents.
  • the oxidation of vilazodone of Formula IV is carried out a temperature of about 10°C to about 40°C, preferably at about 20°C to about 30°C.
  • the oxidation of vilazodone of Formula IV is carried out for about 4 hours to about 8 hours, preferably for about 6 hours.
  • a fourth aspect of the present invention provides a process for the preparation of the oxo vilazodone impurity of Formula III
  • reaction of the intermediate of Formula V with the intermediate of Formula VI is carried out in the presence of a solvent selected from the group consisting of alcohols, amides, halogenated hydrocarbons, esters, or mixtures thereof.
  • a solvent selected from the group consisting of alcohols, amides, halogenated hydrocarbons, esters, 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.
  • halogenated hydrocarbons include dichloromethane, chloroform, or mixtures thereof.
  • esters include ethyl acetate, methyl acetate, isopropyl acetate, or mixtures thereof.
  • N-methylpyrrolidone and 2-propanol are used as solvents.
  • the reaction of the intermediate of Formula V and the intermediate of Formula VI is carried out in the presence of a base.
  • the base is selected from the group consisting of inorganic bases and organic bases.
  • Examples of inorganic bases include hydroxides, carbonates, and bicarbonates of alkali and alkaline earth metals.
  • Examples of hydroxides of alkali and alkaline earth metals include sodium hydroxide, potassium hydroxide, barium hydroxide, or mixtures thereof.
  • Examples of carbonates of alkali and alkaline earth metals include sodium carbonate, potassium carbonate, barium carbonate, or mixtures thereof.
  • Examples of bicarbonates of alkali and alkaline earth metals include sodium bicarbonate, magnesium bicarbonate, potassium bicarbonate, or mixtures thereof.
  • Examples of organic bases include tributyl amine, triethyl amine, ethyl amine, ammonia, diisopropyl ethyl amine, or mixtures thereof. In the preferred embodiment of present invention, tributyl amine is used as the base.
  • reaction of the intermediate of Formula V and the intermediate of Formula VI is carried out at a temperature of about 10°C to about 150°C, preferably at about 20°C to about 130°C.
  • Formula VI is carried out for about 20 minutes to about 30 hours, preferably for about 24 minutes to about 26 hours.
  • a fifth aspect of the present invention provides the use of the vilazodone N-oxide impurity of Formula II or the oxo vilazodone impurity of Formula III as a reference standard for analyzing the purity of vilazodone, salts, or solvates thereof in a sample comprising vilazodone, salts, or solvates thereof.
  • a sixth aspect of the present invention provides the use of the vilazodone N-oxide impurity of Formula II or the oxo vilazodone impurity of Formula III as a reference standard for analyzing the purity of a pharmaceutical composition comprising vilazodone, salts, or solvates thereof.
  • a seventh aspect of the present invention provides a chromatographic method for testing the purity of a sample comprising vilazodone, salts, or solvates thereof by determining the presence of the vilazodone N-oxide impurity of Formula II or the oxo vilazodone impurity of Formula III, comprising the steps of:
  • a reference standard solution comprises the vilazodone N-oxide impurity of Formula II or the oxo vilazodone impurity of Formula III dissolved in a solvent, such as acetonitrile.
  • the presence of the vilazodone N-oxide impurity of Formula II or the oxo vilazodone impurity of Formula III in a sample of vilazodone, salts, or solvates thereof may be determined by chromatographic techniques, such as HPLC, LC-MS, or TLC by comparing the retention time of the different components of a sample of vilazodone, salts, or solvates thereof with the retention time of the vilazodone N-oxide impurity of Formula II or the oxo vilazodone impurity of Formula III.
  • An eighth aspect of the present invention provides a method for preparing vilazodone, salts, or solvates thereof suitable for pharmaceutical use, comprising the steps of:
  • step c) subjecting the vilazodone, salts, or solvates thereof to purification, wherein step c) may be carried out before or after step b).
  • the reference standard solution comprises the vilazodone N-oxide impurity of Formula II or the oxo vilazodone impurity of Formula III dissolved in a solvent, such as acetonitrile.
  • Assessing the purity of vilazodone, salts, or solvates thereof (such as the hydrochloride salt) using the vilazodone N-oxide impurity of Formula II or the oxo vilazodone impurity of Formula III as a reference standard refers to determining the concentration of the vilazodone N-oxide impurity of Formula II or the oxo vilazodone impurity of Formula III in a sample comprising vilazodone, salts, or solvates thereof.
  • the concentration of the vilazodone N-oxide impurity of Formula II or the oxo vilazodone impurity of Formula III is determined by conventional methods known in the art, such as by HPLC or LC-MS.
  • vilazodone, 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 vilazodone N-oxide impurity of Formula II or the oxo vilazodone impurity of Formula III as a reference standard to quantify the amount of the vilazodone N-oxide impurity of Formula II or the oxo vilazodone impurity of Formula III in a sample of vilazodone, salts, or solvates thereof.
  • a ninth aspect of the present invention provides vilazodone free base or its hydrochloride salt substantially free of the vilazodone N-oxide impurity of Formula II or the oxo vilazodone impurity of Formula III.
  • the IR spectrum was recorded using a PerkinElmer ® Spectrum One FT-IR spectrometer.
  • the NMR spectrum was recorded using a Bruker ® Avance III 400 MHz instrument.
  • HPLC purity was determined using an Ascentis ® Express C18, (150 mm x 4.6 mm), 2.7 ⁇ column with a flow rate 0.5 mL/minute - 0.6 mL/minute; Column oven temperature: 35°C; Sample tray temperature: 10°C; Detector: UV at 270 nm; Injection volume: 10 ⁇ ; Run time: 110 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.
  • the crude vilazodone N-oxide was purified by passing it through a YMC-Pack ® ODS-A ® , 15 ⁇ , 500 mm x 30 mm column at ambient temperature using a mixture of 0.5 M KH 2 PO 4 buffer and acetonitrile (60:40% v/v ratio; 2000 mL) as the mobile phase, followed by adjusting the pH of the solution to 5.5 with 10% aqueous ammonia solution (0.2 mL; prepared by dissolving 1 mL of 25% ammonia solution in 10 mL water) to obtain the vilazodone N-oxide of Formula II.
  • Figure 1 provides the HPLC of a standard solution of the vilazodone N-oxide impurity of Formula II.
  • Example 2 HPLC method for the analysis of the vilazodone N-oxide impurity of Formula II
  • the chromatographic separation was carried out using an Ascentis ® Express C 18, 2.7 ⁇ , 150 mm x 4.6 mm column along with a Hypersil ® BDS C18, 5 ⁇ , 20 mm x 4.6 mm guard column at a temperature of 35°C, using a UV detector at a wavelength of 270 nm.
  • the buffer solution was prepared by dissolving ammonium acetate (1.54 g) in water (1000 mL), adjusting the pH of the solution to 5.6 with glacial acetic acid, and filtering the solution through a 0.22 micron filter, or through a finer porosity membrane filter.
  • the mobile phase was prepared by mixing the buffer solution and methanol in a 95:5 ratio (v/v%).
  • the diluent was prepared by dissolving 0.2 % orthophosphoric acid and
  • the analysis of the vilazodone N-oxide impurity of Formula II in a sample of vilazodone hydrochloride was carried out by injecting 10 of the test sample (prepared by dissolving 38 mg of vilazodone hydrochloride in 10 mL of diluent and making up the volume to 50 mL by adding the diluent followed by filtration through a 0.20 ⁇ nylon filter) into the column and running the chromatogram for 110 minutes.
  • the retention time for vilazodone was found to be 63.5 ⁇ 0.5 minutes, and the retention time for vilazodone N-oxide was found to be 46.5 ⁇ 0.5 minutes.
  • Figure 3 provides the HPLC of a sample of a vilazodone active pharmaceutical ingredient containing the vilazodone N-oxide impurity of Formula II and the oxo vilazodone impurity of Formula III.
  • the reaction mixture was stirred for 1 hour, filtered, washed with 2-propanol (20 mL), and then washed with methanol (20 mL) to obtain the crude oxo vilazodone (9.5 g).
  • the crude oxo vilazodone obtained (2 g) was purified by passing it through a YMC-Pack ® ODS-A ® , 15 ⁇ , 500 mm x 30 mm column at ambient temperature, using a mixture of 0.5 M KH 2 PO 4 buffer and acetonitrile (60:40% v/v ratio; 5000 mL) as the mobile phase, followed by adjusting the pH of the solution to 7.5 ⁇ 0.05 with 10% aqueous ammonia solution (0.2 mL; prepared by dissolving 1 mL of 25% ammonia solution in 10 mL water) to obtain the oxo vilazodone impurity of Formula III.
  • Figure 2 provides the High-Performance Liquid Chromatogram (HPLC) of a standard solution of the oxo vilazodone impurity of Formula III.
  • Example 4 HPLC method for the analysis of the oxo vilazodone impurity (Formula III)
  • the chromatographic separation was carried out using an Ascentis ® Express C 18, 2.7 ⁇ , 150 mm x 4.6 mm column along with a Hypersil ® BDS C18, 5 ⁇ , 20 mm x 4.6 mm guard column at a temperature of 35°C, using a UV detector at a wavelength of 270 nm.
  • the buffer solution was prepared by dissolving ammonium acetate (1.54 g) in water (1000 mL), adjusting the pH of the solution to 5.6 with glacial acetic acid, and filtering the solution through a 0.22 micron filter, or a finer porosity membrane filter.
  • the mobile phase was prepared by mixing the buffer solution and methanol in a
  • the diluent was prepared by dissolving 0.2% orthophosphoric acid and acetonitrile in a 50:50 ratio (v/v%).
  • the analysis of the oxo vilazodone impurity of Formula III in a sample of vilazodone hydrochloride was carried out by injecting 10 of the test sample (prepared by dissolving 38 mg of vilazodone hydrochloride in 10 mL of diluent and making up the volume to 50 mL by adding the diluent followed by filtration through a 0.20 ⁇ nylon filter) into the column and running the chromatogram for 110 minutes.
  • the approximate retention time for vilazodone was found to be 63.5 ⁇ 0.5 minutes, and the approximate retention time for the oxo vilazodone impurity of Formula III was found to be 48.8 ⁇ 0.5 minutes.
  • Figure 3 provides the HPLC of a sample of vilazodone active pharmaceutical ingredient containing the vilazodone N-oxide impurity of Formula II and the oxo vilazodone impurity of Formula III.

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Abstract

The present invention relates to isolated vilazodone N-oxide and oxo vilazodone impurities, processes for their preparation, and their use as reference standards in a chromatographic method for testing the purity of a vilazodone active pharmaceutical ingredient or dosage form.

Description

VILAZODONE IMPURITIES, PROCESS FOR THEIR PREPARATION, AND THEIR USE AS REFERENCE STANDARDS
Field of the Invention
The present invention relates to isolated vilazodone N-oxide and oxo vilazodone impurities, processes for their preparation, and their use as reference standards in a chromatographic method for testing the purity of a vilazodone active pharmaceutical ingredient or dosage form.
Background of the Invention
Vilazodone hydrochloride is chemically described as 2-benzofurancarboxamide, 5- [4- [4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-, hydrochloride (1 : 1). Its chemical structure is depicted below in Formula I:
Figure imgf000002_0001
FORMULA I
Vilazodone hydrochloride is marketed in the United States under the brand name Viibryd® and is indicated for the treatment of major depressive disorder (MDD).
Processes for the preparation of vilazodone free base and its hydrochloride salt are described in U.S. Patent Nos. 5,532,241 and 7,834,020.
Summary of the Invention
The present invention relates to isolated vilazodone N-oxide and oxo vilazodone impurities, processes for their preparation, and their use as reference standards in a chromatographic method for testing the purity of a vilazodone active pharmaceutical ingredient or dosage form.
A first aspect of the present invention provides an isolated vilazodone N-oxide impurity of Formula II.
Figure imgf000003_0001
FORMULA II
A second aspect of the present invention provides an isolated oxo vilazodone im urity of Formula III.
Figure imgf000003_0002
FORMULA III
A third aspect of the present invention provides a process for the preparation of the vilazodone N-oxide impurity of Formula II
Figure imgf000003_0003
FORMULA II
comprising the steps of:
a) reacting vilazodone of Formula IV with an oxidizing agent; and
Figure imgf000003_0004
FORMULA IV b) isolating the vilazodone N-oxide impurity of Formula II from the reaction mixture.
A fourth aspect of the present invention provides a process for the preparation of oxo vilazodone im urity of Formula III
Figure imgf000004_0001
FORMULA III
the steps of:
reacting an intermediate of Formula V
Figure imgf000004_0002
FORMULA V
with an intermediate of Formula VI; and
Figure imgf000004_0003
FORMULA VI
b) isolating the oxo vilazodone impurity of Formula III from the reaction mixture.
A fifth aspect of the present invention provides the use of the vilazodone N-oxide impurity of Formula II or the oxo vilazodone impurity of Formula III as a reference standard for analyzing the purity of vilazodone, salts, or solvates thereof.
A sixth aspect of the present invention provides the use of the vilazodone N-oxide impurity of Formula II or the oxo vilazodone impurity of Formula III as a reference standard for analyzing the purity of a pharmaceutical composition comprising vilazodone, salts, or solvates thereof.
A seventh aspect of the present invention provides a chromatographic method for testing the purity of a sample comprising vilazodone, salts, or solvates thereof by determining the presence of the vilazodone N-oxide impurity of Formula II, or the oxo vilazodone impurity of Formula III, comprising the steps of:
a) dissolving vilazodone, salts, or solvates thereof in a solvent to prepare a sample solution;
b) dissolving a sample of the vilazodone N-oxide impurity of Formula II or the oxo vilazodone impurity of Formula III 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 vilazodone N-oxide impurity of Formula II or the oxo vilazodone impurity of Formula III in the sample using the reference standard solution.
An eighth aspect of the present invention provides a method for preparing vilazodone, salts, or solvates thereof suitable for pharmaceutical use, comprising the steps of:
a) preparing vilazodone, salts, or solvates thereof;
b) assessing the purity of the vilazodone, salts, or solvates thereof by using the vilazodone N-oxide impurity of Formula II or the oxo vilazodone impurity of Formula III as a reference standard; and
c) subjecting the vilazodone, salts, or solvates thereof to purification wherein step c) may be carried out before or after step b).
A ninth aspect of the present invention provides vilazodone free base or its hydrochloride salt substantially free of the vilazodone N-oxide impurity of Formula II or the oxo vilazodone impurity of Formula III. Brief Description of the Drawings
Figure 1 : High-Performance Liquid Chromatogram (HPLC) of a standard solution of the vilazodone N-oxide impurity of Formula II.
Figure 2: HPLC of a standard solution of the oxo vilazodone impurity of Formula III. Figure 3: HPLC of a sample of vilazodone active pharmaceutical ingredient containing the vilazodone N-oxide impurity of Formula II and the oxo vilazodone impurity of Formula III.
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 the number ± 10% of the value .
The term "substantially free of the vilazodone N-oxide impurity of Formula II or the oxo vilazodone impurity of Formula III", as used herein, refers to vilazodone, salts, or solvates thereof having less than 1%, preferably less than 0.5%, and the most preferably less than 0.1%, of the vilazodone N-oxide impurity of Formula II or the oxo vilazodone impurity of Formula III. The term "substantially free of the vilazodone N-oxide impurity of Formula II or the oxo vilazodone impurity of Formula III" may also include vilazodone, salts, or solvates thereof having no detectable amount of the vilazodone N-oxide impurity of Formula II or the oxo vilazodone impurity of Formula III.
The term "reference standard", as used herein, refers to the vilazodone N-oxide impurity of Formula II or the oxo vilazodone impurity of Formula III to be used for the qualitative or quantitative analysis of a sample comprising vilazodone, 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 vilazodone, salts, or solvates thereof which has been separated by a chromatographic technique with the retention time of the vilazodone N-oxide impurity of Formula II or the oxo vilazodone impurity of Formula III 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%, and the most preferably less than 0.1%.
A first aspect of the present invention provides an isolated vilazodone N-oxide impurity of Formula II.
Figure imgf000007_0001
FORMULA II
A second aspect of the present invention provides an isolated oxo vilazodone impurity of Formula III.
Figure imgf000007_0002
FORMULA III
A third aspect of the present invention provides a process for the preparation of the vilazodone N-oxide impurity of Formula II
Figure imgf000007_0003
comprising the steps of:
a) reacting vilazodone of Formula IV with an oxidizing agent; and
Figure imgf000008_0001
FORMULA IV
b) isolating the vilazodone N-oxide impurity of Formula II from the reaction mixture.
In an embodiment of this aspect of the present invention, the oxidizing agent may be selected from the group consisting of m-chloroperoxybenzoic acid, hydrogen peroxide, periodic acid, or ozonide. In the preferred embodiment of this aspect of the present invention, m-chloroperoxybenzoic acid is used as the oxidizing agent.
The oxidation of vilazodone of Formula IV may be carried out in the presence of a solvent selected from the group consisting of ketones, alcohols, halogenated hydrocarbons, or mixtures thereof. Examples of ketones include acetone, methyl butyl ketone, methyl isobutyl ketone, or mixtures thereof. Examples of alcohols include methanol, ethanol, 2- propanol, or mixtures thereof. Examples of halogenated hydrocarbons include dichloromethane, chloroform, or mixtures thereof. In a preferred embodiment of the present invention, methanol and acetone are used as solvents.
The oxidation of vilazodone of Formula IV is carried out a temperature of about 10°C to about 40°C, preferably at about 20°C to about 30°C. The oxidation of vilazodone of Formula IV is carried out for about 4 hours to about 8 hours, preferably for about 6 hours.
A fourth aspect of the present invention provides a process for the preparation of the oxo vilazodone impurity of Formula III
Figure imgf000009_0001
FORMULA III
comprising the steps of:
a) reacting an intermediate of Formula V
Figure imgf000009_0002
FORMULA V
intermediate of Formula VI; and
Figure imgf000009_0003
FORMULA VI
b) isolating the oxo vilazodone of Formula III from the reaction mixture.
The reaction of the intermediate of Formula V with the intermediate of Formula VI is carried out in the presence of a solvent selected from the group consisting of alcohols, amides, halogenated hydrocarbons, esters, 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, N-methylpyrrolidone and 2-propanol are used as solvents. The reaction of the intermediate of Formula V and the intermediate of Formula VI is carried out in the presence of a base. The base is selected from the group consisting of inorganic bases and organic bases. Examples of inorganic bases include hydroxides, carbonates, and bicarbonates of alkali and alkaline earth metals. Examples of hydroxides of alkali and alkaline earth metals include sodium hydroxide, potassium hydroxide, barium hydroxide, or mixtures thereof. Examples of carbonates of alkali and alkaline earth metals include sodium carbonate, potassium carbonate, barium carbonate, or mixtures thereof. Examples of bicarbonates of alkali and alkaline earth metals include sodium bicarbonate, magnesium bicarbonate, potassium bicarbonate, or mixtures thereof. Examples of organic bases include tributyl amine, triethyl amine, ethyl amine, ammonia, diisopropyl ethyl amine, or mixtures thereof. In the preferred embodiment of present invention, tributyl amine is used as the base.
The reaction of the intermediate of Formula V and the intermediate of Formula VI is carried out at a temperature of about 10°C to about 150°C, preferably at about 20°C to about 130°C. The reaction of the intermediate of Formula V and the intermediate of
Formula VI is carried out for about 20 minutes to about 30 hours, preferably for about 24 minutes to about 26 hours.
A fifth aspect of the present invention provides the use of the vilazodone N-oxide impurity of Formula II or the oxo vilazodone impurity of Formula III as a reference standard for analyzing the purity of vilazodone, salts, or solvates thereof in a sample comprising vilazodone, salts, or solvates thereof.
A sixth aspect of the present invention provides the use of the vilazodone N-oxide impurity of Formula II or the oxo vilazodone impurity of Formula III as a reference standard for analyzing the purity of a pharmaceutical composition comprising vilazodone, salts, or solvates thereof.
A seventh aspect of the present invention provides a chromatographic method for testing the purity of a sample comprising vilazodone, salts, or solvates thereof by determining the presence of the vilazodone N-oxide impurity of Formula II or the oxo vilazodone impurity of Formula III, comprising the steps of:
a) dissolving vilazodone, salts, or solvates thereof in a solvent to prepare a sample solution; b) dissolving a sample of the vilazodone N-oxide impurity of Formula II or oxo vilazodone impurity of Formula III 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 vilazodone N-oxide impurity of Formula II or the oxo vilazodone impurity of Formula III in the sample using the reference standard solution.
A reference standard solution comprises the vilazodone N-oxide impurity of Formula II or the oxo vilazodone impurity of Formula III dissolved in a solvent, such as acetonitrile.
The presence of the vilazodone N-oxide impurity of Formula II or the oxo vilazodone impurity of Formula III in a sample of vilazodone, salts, or solvates thereof may be determined by chromatographic techniques, such as HPLC, LC-MS, or TLC by comparing the retention time of the different components of a sample of vilazodone, salts, or solvates thereof with the retention time of the vilazodone N-oxide impurity of Formula II or the oxo vilazodone impurity of Formula III.
An eighth aspect of the present invention provides a method for preparing vilazodone, salts, or solvates thereof suitable for pharmaceutical use, comprising the steps of:
a) preparing vilazodone, salts, or solvates thereof;
b) assessing the purity of vilazodone, salts, or solvates thereof by using the vilazodone N-oxide impurity of Formula II or the oxo vilazodone impurity of Formula III as a reference standard; and
c) subjecting the vilazodone, salts, or solvates thereof to purification, wherein step c) may be carried out before or after step b).
The reference standard solution comprises the vilazodone N-oxide impurity of Formula II or the oxo vilazodone impurity of Formula III dissolved in a solvent, such as acetonitrile. Assessing the purity of vilazodone, salts, or solvates thereof (such as the hydrochloride salt) using the vilazodone N-oxide impurity of Formula II or the oxo vilazodone impurity of Formula III as a reference standard refers to determining the concentration of the vilazodone N-oxide impurity of Formula II or the oxo vilazodone impurity of Formula III in a sample comprising vilazodone, salts, or solvates thereof. Preferably, the concentration of the vilazodone N-oxide impurity of Formula II or the oxo vilazodone impurity of Formula III is determined by conventional methods known in the art, such as by HPLC or LC-MS.
The purification of vilazodone, 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 vilazodone N-oxide impurity of Formula II or the oxo vilazodone impurity of Formula III as a reference standard to quantify the amount of the vilazodone N-oxide impurity of Formula II or the oxo vilazodone impurity of Formula III in a sample of vilazodone, salts, or solvates thereof.
A ninth aspect of the present invention provides vilazodone free base or its hydrochloride salt substantially free of the vilazodone N-oxide impurity of Formula II or the oxo vilazodone impurity of Formula III.
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.
The HPLC purity was determined using an Ascentis® Express C18, (150 mm x 4.6 mm), 2.7 μπι column with a flow rate 0.5 mL/minute - 0.6 mL/minute; Column oven temperature: 35°C; Sample tray temperature: 10°C; Detector: UV at 270 nm; Injection volume: 10 μί; Run time: 110 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 vilazodone N-oxide (Formula ID
A reaction mixture of m-chloroperoxy benzoic acid (1.6 g) and methanol (20 mL) was added to a reaction vessel containing vilazodone (2.0 g) and acetone (120 mL) at 25°C to 30°C. The reaction mixture was stirred for 5 hours. The reaction mixture was concentrated under reduced pressure to obtain crude vilazodone N-oxide (3.4 g). The crude vilazodone N-oxide was purified by passing it through a YMC-Pack® ODS-A®, 15 μπι, 500 mm x 30 mm column at ambient temperature using a mixture of 0.5 M KH2PO4 buffer and acetonitrile (60:40% v/v ratio; 2000 mL) as the mobile phase, followed by adjusting the pH of the solution to 5.5 with 10% aqueous ammonia solution (0.2 mL; prepared by dissolving 1 mL of 25% ammonia solution in 10 mL water) to obtain the vilazodone N-oxide of Formula II.
Yield: 9.0%.
¾NMR (400 MHz, CDC13), δ (in ppm): 1.75 (m, 4H), 2.76 (t, 2H), 3.19 (m, 4H), 3.42 (br, 6H), 7.22 (m, 2H), 7.44 (m, 5H), 8.08 (s, H).
Mass: 458.4 [M + H]+; MS/MS: 441.2, 258.2.
IR in KBr, (in cm"1): 3414, (N-H stretching), 2215 (CN stretching), 1686 (-C=0 stretching), 804, 878 (aryl C-H bendings).
Figure 1 provides the HPLC of a standard solution of the vilazodone N-oxide impurity of Formula II.
Example 2: HPLC method for the analysis of the vilazodone N-oxide impurity of Formula II
The chromatographic separation was carried out using an Ascentis® Express C 18, 2.7 μπι, 150 mm x 4.6 mm column along with a Hypersil® BDS C18, 5 μπι, 20 mm x 4.6 mm guard column at a temperature of 35°C, using a UV detector at a wavelength of 270 nm. The buffer solution was prepared by dissolving ammonium acetate (1.54 g) in water (1000 mL), adjusting the pH of the solution to 5.6 with glacial acetic acid, and filtering the solution through a 0.22 micron filter, or through a finer porosity membrane filter.
The mobile phase was prepared by mixing the buffer solution and methanol in a 95:5 ratio (v/v%).
The diluent was prepared by dissolving 0.2 % orthophosphoric acid and
acetonitrile in a 50:50 ratio (v/v%).
The analysis of the vilazodone N-oxide impurity of Formula II in a sample of vilazodone hydrochloride was carried out by injecting 10 of the test sample (prepared by dissolving 38 mg of vilazodone hydrochloride in 10 mL of diluent and making up the volume to 50 mL by adding the diluent followed by filtration through a 0.20 μπι nylon filter) into the column and running the chromatogram for 110 minutes. The retention time for vilazodone was found to be 63.5 ± 0.5 minutes, and the retention time for vilazodone N-oxide was found to be 46.5 ± 0.5 minutes.
Figure 3 provides the HPLC of a sample of a vilazodone active pharmaceutical ingredient containing the vilazodone N-oxide impurity of Formula II and the oxo vilazodone impurity of Formula III.
Example 3 : Preparation of oxo vilazodone impurity (Formula III)
5-(Piperazin-l-yl)-l-benzofuran-2-carboxamide of Formula V (10.0 g) and 3-(4- chlorobutanoyl)-lH-indole-5-carbonitrile of Formula VI (11.1 g) were added to N-methyl pyrrolidone (50 mL), followed by the addition of tributyl amine (7.6 g) at 25°C to 30°C. The reaction mixture was stirred at 120°C to 130°C for 24 hours. The reaction mixture was cooled to 25°C to 30°C. 2-Propanol (100 mL) and 2-propanolic hydrochloric acid solution (15 mL; 20%) were added to the reaction mixture at 25°C to 30°C. The reaction mixture was stirred for 1 hour, filtered, washed with 2-propanol (20 mL), and then washed with methanol (20 mL) to obtain the crude oxo vilazodone (9.5 g). The crude oxo vilazodone obtained (2 g) was purified by passing it through a YMC-Pack® ODS-A®, 15 μπι, 500 mm x 30 mm column at ambient temperature, using a mixture of 0.5 M KH2PO4 buffer and acetonitrile (60:40% v/v ratio; 5000 mL) as the mobile phase, followed by adjusting the pH of the solution to 7.5 ± 0.05 with 10% aqueous ammonia solution (0.2 mL; prepared by dissolving 1 mL of 25% ammonia solution in 10 mL water) to obtain the oxo vilazodone impurity of Formula III.
Yield: 7.0%
¾NMR (400 MHz, CDC13), δ (in ppm): 2.05 (m, 2H), 2.56 (t, 2H), 2.70 (t, 4H), 3.01 (t, 2H), 3.13 (t, 4H), 7.19 (m, 2H), 7.53 (m, 4H), 8.38 (s, 1H), 8.67 (m, 1H).
Mass: 456.4 [M + H]+; MS/MS: 211.1, 169.0.
IR in KBr, (in cm"1): 3418 (N-H stretching), 2221 (CN stretching), 1669, 1616 (-C=0 stretchings), 808, 887 (aryl C-H bendings).
Figure 2 provides the High-Performance Liquid Chromatogram (HPLC) of a standard solution of the oxo vilazodone impurity of Formula III.
Example 4: HPLC method for the analysis of the oxo vilazodone impurity (Formula III)
The chromatographic separation was carried out using an Ascentis® Express C 18, 2.7 μιη, 150 mm x 4.6 mm column along with a Hypersil® BDS C18, 5 μιη, 20 mm x 4.6 mm guard column at a temperature of 35°C, using a UV detector at a wavelength of 270 nm.
The buffer solution was prepared by dissolving ammonium acetate (1.54 g) in water (1000 mL), adjusting the pH of the solution to 5.6 with glacial acetic acid, and filtering the solution through a 0.22 micron filter, or a finer porosity membrane filter.
The mobile phase was prepared by mixing the buffer solution and methanol in a
95:5 ratio (v/v%).
The diluent was prepared by dissolving 0.2% orthophosphoric acid and acetonitrile in a 50:50 ratio (v/v%).
The analysis of the oxo vilazodone impurity of Formula III in a sample of vilazodone hydrochloride was carried out by injecting 10 of the test sample (prepared by dissolving 38 mg of vilazodone hydrochloride in 10 mL of diluent and making up the volume to 50 mL by adding the diluent followed by filtration through a 0.20 μπι nylon filter) into the column and running the chromatogram for 110 minutes. The approximate retention time for vilazodone was found to be 63.5 ± 0.5 minutes, and the approximate retention time for the oxo vilazodone impurity of Formula III was found to be 48.8 ± 0.5 minutes.
Figure 3 provides the HPLC of a sample of vilazodone active pharmaceutical ingredient containing the vilazodone N-oxide impurity of Formula II and the oxo vilazodone impurity of Formula III.

Claims

Claims:
1. An isolated vilazodone N-oxide impurity of Formula II.
Figure imgf000017_0001
2. An isolated oxo vilazodone impurity of Formula III.
Figure imgf000017_0002
3. A process for the reparation of the vilazodone N-oxide impurity of Formula II
Figure imgf000017_0003
FORMULA II
comprising the steps of:
a) reacting vilazodone of Formula IV with an oxidizing agent; and
Figure imgf000018_0001
b) isolating the vilazodone N-oxide impurity of Formula II from the reaction mixture.
4. The process according to claim 3, wherein the oxidizing agent is selected from the group consisting of m-chloroperoxybenzoic acid, hydrogen peroxide, periodic acid, and ozonide.
5. The process according to claim 3, wherein the oxidation of vilazodone of Formula IV is carried out in the presence of a solvent selected from the group consisting of ketones, alcohols, halogenated hydrocarbons, and mixtures thereof.
6. The process according to claim 5, wherein the ketone is selected from the group consisting of acetone, methyl butyl ketone, methyl isobutyl ketone, and mixtures thereof.
7. The process according to claim 5, wherein the alcohol is selected from the group consisting of methanol, ethanol, 2-propanol, and mixtures thereof.
8. The process according to claim 5, wherein the halogenated hydrocarbon is selected from the group consisting of dichloromethane, chloroform, and mixtures thereof.
9. The process according to claim 5, wherein the solvent is a mixture of methanol and acetone.
10. A rocess for the preparation of an oxo vilazodone impurity of Formula III
Figure imgf000018_0002
comprising the steps of:
a) reacting an intermediate of Formula V
Figure imgf000019_0001
FORMULA V
with an intermediate of Formula VI; and
Figure imgf000019_0002
FORMULA VI
b) isolating the oxo vilazodone impurity of Formula III from the reaction
mixture.
11. The process according to claim 10, wherein the reaction of the intermediate of Formula V and the intermediate of Formula VI is carried out in the presence of a solvent selected from the group consisting of alcohols, amides, halogenated hydrocarbons, esters, and mixtures thereof.
12. The process according to claim 11, wherein the alcohol is selected from the group consisting of methanol, ethanol, 2-propanol, 1-propanol, butanol, and mixtures thereof.
13. The process according to claim 11, wherein the amide is selected from the group consisting of N-methylpyrrolidone, dimethyl acetamide, dimethyl formamide, and mixtures thereof.
14. The process according to claim 11, wherein the halogenated hydrocarbon is selected from the group consisting of dichloromethane, chloroform, and mixtures thereof.
15. The process according to claim 11, wherein the ester is selected from the group consisting of ethyl acetate, methyl acetate, isopropyl acetate, and mixtures thereof.
16. The process according to claim 11, wherein N-methylpyrrolidone and 2-propanol are used as solvents.
17. Use of the vilazodone N-oxide impurity of Formula II or the oxo vilazodone impurity of Formula III as a reference standard for analyzing the purity of vilazodone, salts, or solvates thereof in a sample comprising vilazodone, salts, or solvates thereof.
18. Use of the vilazodone N-oxide impurity of Formula II or the oxo vilazodone impurity of Formula III as a reference standard for analyzing the purity of a
pharmaceutical composition comprising vilazodone, salts, or solvates thereof.
19. A chromatographic method for testing the purity of a sample comprising vilazodone, salts, or solvates thereof by determining the presence of the vilazodone N- oxide impurity of Formula II or the oxo vilazodone impurity of Formula III, comprising the steps of:
a) dissolving vilazodone, salts, or solvates thereof in a solvent to prepare a sample solution;
b) dissolving a sample of the vilazodone N-oxide impurity of Formula II or the oxo vilazodone impurity of Formula III 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 vilazodone N-oxide impurity of Formula II or the oxo vilazodone impurity of Formula III in the sample using the reference standard solution.
20. The process according to claim 19, wherein the reference standard solution comprises a solution of the vilazodone N-oxide impurity of Formula II or oxo vilazodone impurity of Formula III in acetonitrile.
21. A method for preparing vilazodone, salts, or solvates thereof suitable for pharmaceutical use, comprising the steps of:
a) preparing vilazodone, salts, or solvates thereof; b) assessing the purity of vilazodone, salts, or solvates thereof by using the vilazodone N-oxide impurity of Formula II or the oxo vilazodone impurity of Formula III as a reference standard; and
c) subjecting the vilazodone, salts, or solvates thereof to purification, wherein step c) may be carried out before or after step b).
22. Vilazodone free base or its hydrochloride salt substantially free of the vilazodone N-oxide impurity of Formula II or the oxo vilazodone impurity of Formula III.
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CN105801566A (en) * 2014-12-30 2016-07-27 山东方明药业集团股份有限公司 Preparation method of vilazodone hydrochloride
CN106632279A (en) * 2016-12-01 2017-05-10 北京万全德众医药生物技术有限公司 Preparation method for vilazodone monoxide
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