WO2014178013A1 - Impuretés de vilazodone, procédé pour leur préparation et leur utilisation comme normes de référence - Google Patents

Impuretés de vilazodone, procédé pour leur préparation et leur utilisation comme normes de référence 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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PCT/IB2014/061113
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English (en)
Inventor
Pratibha Singh
Kaushal Nayyar
Bindu Srivastava
Sandeep TOMAR
Rajesh Kumar Thaper
Mohan Prasad
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Ranbaxy Laboratories Limited
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Publication of WO2014178013A1 publication Critical patent/WO2014178013A1/fr

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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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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des impuretés isolées de N-oxyde de vilazodone et oxo vilazodone, leurs procédés de préparation et leur utilisation en tant que normes de référence dans un procédé chromatographique pour tester la pureté d'un ingrédient pharmaceutique actif ou une forme de dosage à base de vilazodone.
PCT/IB2014/061113 2013-04-30 2014-04-30 Impuretés de vilazodone, procédé pour leur préparation et leur utilisation comme normes de référence WO2014178013A1 (fr)

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Cited By (3)

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Publication number Priority date Publication date Assignee Title
CN105801566A (zh) * 2014-12-30 2016-07-27 山东方明药业集团股份有限公司 一种盐酸维拉佐酮的制备方法
CN106632279A (zh) * 2016-12-01 2017-05-10 北京万全德众医药生物技术有限公司 维拉佐酮单氧化物的制备方法
CN114702510A (zh) * 2022-05-05 2022-07-05 重庆华邦胜凯制药有限公司 一种利福布汀氧化杂质的制备方法

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US7834020B2 (en) 2001-06-19 2010-11-16 Merck Patent Gesellschaft Polymorphic forms of 1-′4-(5-cyanoindol-3-yl)butyl-4-(2-carbamoylbenzofuran-5-yl) piperazine hydrochloride
WO2012131706A1 (fr) * 2011-03-20 2012-10-04 Cadila Healthcare Limited Forme amorphe du chlorhydrate de vilazodone et son procédé de préparation

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105801566A (zh) * 2014-12-30 2016-07-27 山东方明药业集团股份有限公司 一种盐酸维拉佐酮的制备方法
CN106632279A (zh) * 2016-12-01 2017-05-10 北京万全德众医药生物技术有限公司 维拉佐酮单氧化物的制备方法
CN114702510A (zh) * 2022-05-05 2022-07-05 重庆华邦胜凯制药有限公司 一种利福布汀氧化杂质的制备方法
CN114702510B (zh) * 2022-05-05 2023-06-30 重庆华邦胜凯制药有限公司 一种利福布汀氧化杂质的制备方法

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