WO2011061545A1 - Procédé hplc pour l'analyse de vorinostat - Google Patents

Procédé hplc pour l'analyse de vorinostat Download PDF

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Publication number
WO2011061545A1
WO2011061545A1 PCT/GB2010/051931 GB2010051931W WO2011061545A1 WO 2011061545 A1 WO2011061545 A1 WO 2011061545A1 GB 2010051931 W GB2010051931 W GB 2010051931W WO 2011061545 A1 WO2011061545 A1 WO 2011061545A1
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WO
WIPO (PCT)
Prior art keywords
acid
hplc method
octanediamide
vorinostat
liquid
Prior art date
Application number
PCT/GB2010/051931
Other languages
English (en)
Inventor
Erra Koteswara Satya Vijayakumar
Vinayak Vele
Manish Singh
Sachin Vishe
Original Assignee
Generics [Uk] Limited
Mylan India Private Limited
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Filing date
Publication date
Application filed by Generics [Uk] Limited, Mylan India Private Limited filed Critical Generics [Uk] Limited
Publication of WO2011061545A1 publication Critical patent/WO2011061545A1/fr

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/26—Conditioning of the fluid carrier; Flow patterns
    • G01N30/28—Control of physical parameters of the fluid carrier
    • G01N30/36—Control of physical parameters of the fluid carrier in high pressure liquid systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/26—Conditioning of the fluid carrier; Flow patterns
    • G01N30/28—Control of physical parameters of the fluid carrier
    • G01N30/34—Control of physical parameters of the fluid carrier of fluid composition, e.g. gradient

Definitions

  • the current invention relates to new HPLC methods for the analysis of the drug substance vorinostat and related substances.
  • the mobile phase comprises two or more liquids and the relative concentration of the liquids is varied to a predetermined gradient.
  • the mobile phase comprises an alcohol.
  • the mobile phase comprises a phosphate salt, a phosphoric acid or an anhydride thereof.
  • the current invention also relates to a method for analysing a substance, comprising the detection and optional quantification of one or more specific impurities.
  • the current invention further relates to the use of specific substances as reference standards and markers, and to vorinostat and associated pharmaceutical compositions that have been analysed by the methods of the current invention and/ or are substantially free of specific impurities.
  • the likely impurities in APIs and pharmaceutical compositions include residual quantities of synthetic precursors (intermediates), by-products which arise during the synthesis of the API, residual solvents, isomers of the API (e.g. geometrical isomers, diastereomers or enantiomers), contaminants which are present in materials used in the synthesis of the API or in the preparation of the pharmaceutical composition, and unidentified adventitious substances.
  • isomers of the API e.g. geometrical isomers, diastereomers or enantiomers
  • contaminants which are present in materials used in the synthesis of the API or in the preparation of the pharmaceutical composition and unidentified adventitious substances.
  • Other impurities which may appear on storage include degradants of the API, for instance formed by hydrolysis or oxidation.
  • the tests that are required to demonstrate that die API or pharmaceutical compositions are safe and effective include a purity/ assay test, a related substances test, a content uniformity test and a dissolution test.
  • the purity/ ssay test determines the purity of the test product when compared to a standard of a known purity, while the related substances test is used to quantify all the impurities present in the product.
  • the content uniformity test ensures that batches of product like a tablet contain a uniform amount of API, and the dissolution test ensures that each batch of product has a consistent dissolution and release of the API.
  • the technique of choice for the analysis of API or a pharmaceutical composition e.g. a tablet or capsule
  • HPLC High Performance Liquid Chromatography
  • the API and the impurities present, if any, are separated on the HPLC stationary phase and they can be detected and quantified using their response obtained from the UV- Visible detector.
  • HPLC is a chromatographic separation technique in which high-pressure pumps force the substance or mixture being analysed together with a mobile phase, also referred to as the eluent, through a separating column containing the stationary phase.
  • HPLC analysis may be performed in isocratic or gradient mode. In isocratic mode, the mobile phase composition is constant throughout.
  • a gradient HPLC mode is carried out by a gradual change over a period of time in the percentage of the two or more solvents maldng up the mobile phase. The change in solvent is controlled by a mixer which mixes the solvents to produce the mobile phase prior to its passing through the column.
  • a substance interacts strongly with the stationary phase, it remains in the column for a relatively long time, whereas a substance that does not interact as strongly with the stationary phase elutes out of the column sooner.
  • the various constituents of the analyte appear at the end of the separating column at different times, known as retention times, where they can be detected and quantified by means of a suitable detector, such as a UV- Visible detector.
  • Vorinostat (I) chemically known as N-hydroxy-N'-phenyl-octanediamide or suberoylanilide hydroxamic acid (SAHA), is an orally active 5-hydroxytriptamine (5-HT) receptor agonist and is used for the treatment of cutaneous T-cell lymphoma (CTCL).
  • CTCL cutaneous T-cell lymphoma
  • HPLC methods disclosed in the prior art are not suitable for the detection and estimation of total impurities that are present in a vorinostat sample synthesised by preferred synthetic routes, particularly the route disclosed in co-pending patent application WO 2010/043904.
  • HPLC methods reported in the prior art are not particularly convenient or suitable for analysing vorinostat as an API, particularly with respect to related substances. Consequently, although HPLC methods have been reported in the literature for the analysis of vorinostat and its impurities, there is still a need for an alternative method which avoids the problems associated with the known methods as discussed above.
  • a particular object of the invention is to provide a new, accurate and sensitive HPLC method for the detection and quantitation of intermediates and related substances that are formed and may remain in the batches of vorinostat synthesised by the process disclosed in co-pending patent application WO 2010/043904.
  • vorinostat as used herein throughout the description and claims means vorinostat and/ or any salt, tautomer, solvate, hydrate, anhydrate or polymorphic form thereof unless explicitly stated otherwise.
  • the current invention is particularly useful for the analysis of vorinostat.
  • a first aspect of the current invention provides a HPLC method for analysing vorinostat, or a salt thereof, wherein the mobile phase comprises two or more liquids and the relative concentration of the liquids is varied to a predetermined gradient.
  • the method is used for analysing vorinostat.
  • the mobile phase comprises a first liquid A which is aqueous based, such as water or an aqueous solution of a buffer.
  • the buffer is an acid or an organic salt or an inorganic salt or a mixture thereof.
  • the buffer is a phosphate salt, an acetate salt, a trifluoroacetate salt, a formate salt, acetic acid, trifluoroacetic acid, formic acid, a phosphoric acid or a mixture thereof. More typically, the buffer is a phosphate salt, an acetate salt, a formate salt, acetic acid, trifluoroacetic acid, orthophosphoric acid or a mixture thereof.
  • the buffer is a phosphate salt, a phosphoric acid or an anhydride thereof, such as orthophosphoric acid, pyrophosphoric acid, tripolyphosphoric acid, tetrapolyphosphoric acid, trimetaphosphoric acid or phosphoric anhydride.
  • the buffer is an acid, such as orthophosphoric acid.
  • the buffer can be present at a concentration of 0.001 to 0.2 % w/v, preferably at a concentration of 0.005 to 0.1 % w/v, more preferably at a concentration of 0.01 to 0.1 % w/v, most preferably at a concentration of about 0.05 % w/v.
  • the buffer is orthophosphoric acid at a concentration of 0.01 to 0.2 % w/v.
  • the buffer is orthophosphoric acid present at a concentration of about
  • the pH of the buffer solution is approximately 2 to 6. More preferably the pH of the buffer solution is approximately 2 to 4. More preferably still the pH of the buffer solution is approximately 2 to 3. Most preferably the pH of the buffer solution is approximately 2.3.
  • the method of the first aspect of the current invention is carried out at a column temperature between approximately 15 to 40°C.
  • the mobile phase preferably comprises a second liquid B which is or comprises an organic solvent, such as methanol, acetonitrile, propanol or isopropanol or a mixture thereof.
  • the second liquid B comprises a polar protic solvent such as acetic acid, methanol, ethanol, n-propanol or isopropanol, and/or a dipolar aprotic solvent such as acetone, acetonitrile, dimethoxyethane, DMF, DMSO, 1,4-dioxane, pyridine, or THF.
  • a polar protic solvent such as acetic acid, methanol, ethanol, n-propanol or isopropanol
  • a dipolar aprotic solvent such as acetone, acetonitrile, dimethoxyethane, DMF, DMSO, 1,4-dioxane, pyridine, or THF.
  • the second liquid B comprises both a polar protic solvent and a dipolar aprotic solvent.
  • the polar protic solvent is not an acid.
  • the polar protic solvent is an alcohol, preferably one containing from 1 to 6 carbon atoms, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, tert-butanol or a mixture thereof. Most preferably the polar protic solvent is methanol.
  • the second liquid B comprises a dipolar aprotic solvent
  • the dipolar aprotic solvent is acetonitrile
  • the second liquid is a mixture of acetonitrile and methanol.
  • the second liquid B is a mixture of acetonitrile and methanol, preferably in the ratio of 5:95 to 50:50 acetonitrile:methanol v/v, more preferably in the ratio of about 10:90 acetonitrile:methanol v/v.
  • the second liquid B is substantially water miscible.
  • the magnitude of ⁇ ⁇ is at least 0.10, more preferably at least 0.25, more preferably at least 0.50, more preferably at least 0.75, more preferably at least 0.90, even more preferably at least 0.95.
  • the term "substantially miscible" in relation to two liquids X and Y means that when mixed together at 20°C and 1 atmosphere pressure, X and Y form a single phase when mixed together in any proportion.
  • Preferred embodiments of the first aspect of the current invention are when the first liquid A is an aqueous solution of orthophosphoric acid, preferably at a concentration of about 0.05 % w/v, and the second liquid B is a mixture of acetonitrile and methanol, preferably in the ratio of about 10:90 acetonitrile:methanol v/v.
  • a mobile phase flow rate of between 0.01 and 10 ml/min is used, more preferably a mobile phase flow rate of between 0.1 and 4 ml/min is used, more preferably a mobile phase flow rate of about 1 ml/ min is used.
  • the method of the current invention comprises a gradient programming so that the relative concentration of the liquids A and B by volume is typically varied to a gradient between 100 % A : 0 % B to 0 % A : 100 % B over a period of 10 to 180 minutes.
  • the gradient is between 100 % A : 0 % B to 0 % A : 100 % B over a period of 25 to 120 minutes, more preferably between 100 % A : 0 % B to 0 % A : 100 % B over a period of 25 to 60 minutes.
  • the first aspect of the current invention may comprise a gradient programming so that the relative concentration of the liquids A and B by volume is varied to a gradient starting at relative concentrations of 50-70 % A : 30-50 % B and finishing at relative concentrations of 20-40 % A : 60-80% B.
  • the gradient starts at relative concentrations of 55-65 % A : 35-45 % B and finishes at 25-35 % A : 65-75 % B.
  • the gradient starts at relative concentrations of about 60 % A : 40 % B and finishes at relative concentrations of about 30 % A : 70 % B.
  • the variation in gradient may typically take place over 10 to 180 minutes, preferably over 15 to 60 minutes, more preferably over 20 to 30 minutes.
  • a particularly preferred embodiment of the first aspect of the current invention is when the first liquid A is about 0.05 % w/v aqueous orthophosphoric acid and the second liquid B is a mixture of acetonitrile and methanol in the ratio of about 10:90 acetonitrile:mefhanol v/v.
  • the stationary phase used is a gel, preferably a silica gel.
  • the stationary phase used in the first aspect of the current invention is reverse phase such as octadecylsilyl silica gel, octylsilyl silica gel, phenylalkyl silica gel, cyanopropyl silica gel, aminopropyl silica gel or an alkyl-diol silica gel.
  • Particularly suitable stationary phases include octadecylsilyl silica gel or octylsilyl silica gel.
  • a particularly preferred stationary phase comprises a Cosmosil 5C lg -MS-II (150 mm x 4.6 mm), 5 ⁇ column, preferably with a pore size of about 120A.
  • the stationary phase has a particle size of between 0.1 and ⁇ , or between 0.5 and 25 ⁇ , or between 1 and ⁇ . More preferably the stationary phase has a particle size of about 5 ⁇ .
  • the stationary phase has a pore size of between 10 and ⁇ , or between 25 and 500A, or between 50 and 20 ⁇ . More preferably the stationary phase has a pore size of about 120A.
  • the chromatography is carried out in a column between 10mm and 5000mm in length, or in a column between 50mm and 500mm in length, or between 100mm and 250mm in length. More preferably the chromatography is carried out in a column about 150mm in length.
  • the chromatography may be carried out in a column between 0.01mm and 100mm in internal diameter, or between 0.1mm and 50mm in internal diameter, or between 1mm and 10mm in internal diameter. More preferably the chromatography is carried out in a column about 4.6mm in internal diameter.
  • a particularly preferred method according to the first aspect of the current invention is when the first liquid A is about 0.05 % w/v aqueous orfhophosphoric acid and the second liquid B is a mixture of acetonitrile and methanol in the ratio of about 10:90 acetonitrile:methanol v/v and the gradient is as follows:
  • a more preferred method according to the first aspect of the current invention is when the first liquid A is about 0.05 % w/v aqueous orthophosphoric acid and the second liquid B is a mixture of acetonitrile and methanol in the ratio of about 10:90 acetonitrile:methanol v/v and the gradient is as follows:
  • the eluent may be analysed by a detector such as a UV and/ or visible spectrophotometer, a fluorescence spectrophotometer, a differential refractometer, an electrochemical detector, a mass spectrometer, a light scattering detector or a radioactivity detector.
  • a detector such as a UV and/ or visible spectrophotometer, a fluorescence spectrophotometer, a differential refractometer, an electrochemical detector, a mass spectrometer, a light scattering detector or a radioactivity detector.
  • the HPLC method according to the first aspect of the current invention efficiently detects and quantifies in a single run all impurities including those selected from the following compounds: 1) ⁇ , ⁇ '-diphenyl-octanediamide
  • one or more of the following compounds are used as internal or external reference marker(s) or as internal or external reference standard(s):
  • the HPLC method is used for the analysis of vorinostat that is suitable for use in a pharmaceutical composition.
  • the HPLC method is used for the analysis of vorinostat that has not entered the human or animal body.
  • the vorinostat that is analysed is not in contact with a human or animal bodily fluid such as plasma.
  • the vorinostat that is analysed is not in solution.
  • the HPLC method is used for the analysis of a pharmaceutical composition comprising vorinostat.
  • the HPLC method is used for the analysis of a substance comprising at least 5% vorinostat by weight.
  • the substance comprises at least 10%, at least 25%, at least 50%, at least 75% or at least 90% vorinostat by weight.
  • the substance comprises at least 95% vorinostat by weight.
  • the chromatographic method is used for the analysis of a substance comprising vorinostat as the only active pharmaceutical ingredient.
  • a second aspect of the current invention provides a chromatographic method for analysing vorinostat, or a salt thereof, wherein the mobile phase comprises an alcohol.
  • the alcohol preferably contains from 1 to 6 carbon atoms. More preferably the alcohol is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, tert- butanol and mixtures thereof. Most preferably the alcohol is methanol.
  • the mobile phase comprises two or more liquids, including a first liquid A and a second liquid B, wherein at least one of said liquids comprises the alcohol.
  • the first liquid A is aqueous based, such as water or an aqueous solution of a buffer.
  • the buffer is an acid or an organic salt or an inorganic salt or a mixture thereof.
  • die buffer is a phosphate salt, an acetate salt, a trifiuoroacetate salt, a formate salt, acetic acid, trifiuoroacetic acid, formic acid, a phosphoric acid or a mixture thereof. More typically, the buffer is a phosphate salt, an acetate salt, a formate salt, acetic acid, trifiuoroacetic acid, orthophosphoric acid or a mixture thereof.
  • the buffer is a phosphate salt, a phosphoric acid or an anhydride thereof, such as orthophosphoric acid, pyrophosphoric acid, tripolyphosphoric acid, tetrapolyphosphoric acid, trimetaphosphoric acid or phosphoric anhydride.
  • the buffer is an acid, such as orthophosphoric acid.
  • the buffer can be present at a concentration of 0.001 to 0.2 % w/v, preferably at a concentration of 0.005 to 0.1 % w/v, more preferably at a concentration of 0.01 to 0.1 % w/v, most preferably at a concentration of about 0.05 % w/v.
  • the buffer is orthophosphoric acid at a concentration of 0.01 to 0.2 % w/v.
  • the buffer is orthophosphoric acid present at a concentration of about
  • the pH of the buffer solution is approximately 2 to 6. More preferably the pH of the buffer solution is approximately 2 to 4. More preferably still the pH of the buffer solution is approximately 2 to 3. Most preferably the pH of the buffer solution is approximately 2.3.
  • the second liquid B comprises the alcohol.
  • the second liquid B comprises the alcohol and a dipolar aprotic solvent such as acetone, acetonitrile, dimethoxyethane, DMF, DMSO, 1,4-dioxane, pyridine, or THF.
  • a dipolar aprotic solvent such as acetone, acetonitrile, dimethoxyethane, DMF, DMSO, 1,4-dioxane, pyridine, or THF.
  • the dipolar aprotic solvent is acetonitrile.
  • the second liquid B is a mixture of acetonitrile and methanol, preferably in the ratio of 5:95 to 50:50 acetonitrile:mefhanol v/v, more preferably in the ratio of about 10:90 acetonitrile:methanol v/v.
  • the second liquid B is substantially water miscible.
  • Preferred embodiments of the second aspect of the current invention are when the first liquid A is an aqueous solution of orthophosphoric acid, preferably at a concentration of about 0.05 % w/v, and the second liquid B is a mixture of acetonitrile and methanol, preferably in the ratio of about 10:90 acetonitrile:methanol v/v.
  • the chromatographic method is a liquid chromatographic method such as a HPLC, LC-MS or LC-MS/MS method; preferably the chromatographic method is a HPLC method.
  • the chromatographic method may be an isocratic method, preferably such that the relative concentration of the liquids A and B by volume is set between 99.5%A : 0.5%B and 0.5%A : 99.5%B, or between 90%A : 10%B and 10%A : 90%B, more preferably between 75%A : 25%B and 25%A : 75%B. More preferably the relative concentration of the liquids A and B by volume is about 45%A : 55%B.
  • the relative concentration of the liquids in the mobile phase may be varied to a predetermined gradient.
  • the relative concentration of the liquids A and B by volume is varied to a gradient between 100 % A : 0 % B to 0 % A : 100 % B over a period of 10 to 180 minutes.
  • the gradient is between 100 % A : 0 % B to 0 % A : 100 % B over a period of 25 to 120 minutes, more preferably between 100 % A : 0 % B to 0 % A : 100 % B over a period of 25 to 60 minutes.
  • the second aspect of the current invention may comprise a gradient programming so that the relative concentration of the liquids A and B by volume is varied to a gradient starting at relative concentrations of 50-70 % A : 30-50 % B and finishing at relative concentrations of 20-40 % A : 60-80% B.
  • the gradient starts at relative concentrations of 55-65 % A : 35-45 % B and finishes at 25-35 % A : 65-75 % B.
  • the gradient starts at relative concentrations of about 60 % A : 40 % B and finishes at relative concentrations of about 30 % A : 70 % B.
  • the variation in gradient may typically take place over 10 to 180 minutes, preferably over 15 to 60 minutes, more preferably over 20 to 30 minutes.
  • a particularly preferred method according to the second aspect of the current invention is when the first liquid A is about 0.05 % w/v aqueous or triphosphoric acid and the second liquid B is a mixture of acetonitrile and methanol in the ratio of about 10:90 acetonitrile:methanol v/v and the gradient is as follows:
  • a more preferred method according to the second aspect of the current invention is when the first liquid A is about 0.05 % ⁇ v/v aqueous orthophosphoric acid and the second liquid B is a mixture of acetonitrile and methanol in the ratio of about 10:90 acetonitrile:methanol v/v and the gradient is as follows:
  • the method of the second aspect of the current invention is carried out at a column temperature between approximately 15 to 40°C.
  • a mobile phase flow rate of between 0.01 and 10 ml/min is used, more preferably a mobile phase flow rate of between 0.1 and 4 ml/min is used, more preferably a mobile phase flow rate of about 1 ml/ min is used.
  • the stationary phase used is a gel, preferably a silica gel.
  • the stationary phase used in the second aspect of the current invention is reverse phase such as octadecylsilyl silica gel, octylsilyl silica gel, phenylalkyl silica gel, cyanopropyl silica gel, aminopropyl silica gel or an alkyl-diol silica gel.
  • Particularly suitable stationary phases include octadecylsilyl silica gel or octylsilyl silica gel.
  • a particularly preferred stationary phase comprises a Cosmosil 5C 18 -MS-II (150 mm x 4.6 mm), 5 ⁇ column, preferably with a pore size of about 12 ⁇ .
  • the stationary phase has a particle size of between 0.1 and ⁇ , or between 0.5 and 25 ⁇ , or between 1 and ⁇ . More preferably the stationary phase has a particle size of about 5 ⁇ .
  • the stationary phase has a pore size of between 10 and ⁇ , or between 25 and 50 ⁇ , or between 50 and 20 ⁇ . More preferably the stationary phase has a pore size of about 120A.
  • the chromatography is carried out in a column between 10mm and 5000mm in length, or in a column between 50mm and 500mm in length, or between 100mm and 250mm in length. More preferably the chromatography is carried out in a column about 150mm in length.
  • the chromatography may be carried out in a column between 0.01mm and 100mm in internal diameter, or between 0.1mm and 50mm in internal diameter, or between 1mm and 10mm in internal diameter. More preferably the chromatography is carried out in a column about 4.6mm in internal diameter.
  • the eluent may be analysed by a detector such as a UV and/ or visible spectrophotometer, a fluorescence spectrophotometer, a differential refractometer, an electrochemical detector, a mass spectrometer, a light scattering detector or a radioactivity detector.
  • a detector such as a UV and/ or visible spectrophotometer, a fluorescence spectrophotometer, a differential refractometer, an electrochemical detector, a mass spectrometer, a light scattering detector or a radioactivity detector.
  • N-hydroxy-N,N-di-(N'-phenyl-octanediamide) amine N-hydroxy-N,N-di-(N'-phenyl-octanediamide) amine.
  • the chromatographic method is used for the analysis of vorinostat that is suitable for use in a pharmaceutical composition.
  • the chromatographic method is used for the analysis of vorinostat that has not entered the human or animal body.
  • the vorinostat that is analysed is not in contact with a human or animal bodily fluid such as plasma.
  • the vorinostat that is analysed is not in solution.
  • the chromatographic method is used for the analysis of a pharmaceutical composition comprising vorinostat.
  • the chromatographic method is used for the analysis of a substance comprising at least 5% vorinostat by weight.
  • the substance comprises at least 10%, at least 25%, at least 50%, at least 75% or at least 90% vorinostat by weight.
  • the substance comprises at least 95% vorinostat by weight.
  • the chromatographic method is used for the analysis of a substance comprising vorinostat as the only active pharmaceutical ingredient.
  • a third aspect of the current invention provides a chromatographic method for analysing vorinostat, or a salt thereof, wherein the mobile phase comprises a phosphate salt, a phosphoric acid or an anhydride thereof, such as orthophosphoric acid, pyrophosphoric acid, tripolyphosphoric acid, tetrapolyphosphoric acid, trimetaphosphoric acid or phosphoric anhydride.
  • the mobile phase comprises orthophosphoric acid.
  • the mobile phase further comprises water.
  • die mobile phase comprises an aqueous solution of the phosphate salt, phosphoric acid or anhydride thereof.
  • the mobile phase comprises an aqueous solution of orthophosphoric acid.
  • the phosphate salt, phosphoric acid or anhydride thereof can be present in the aqueous solution at a concentration of 0.001 to 0.2 % w/v, preferably at a concentration of 0.005 to 0.1 % w/v, more preferably at a concentration of 0.01 to 0.1 % w/v, most preferably at a concentration of about 0.05 % w/v.
  • the orthophosphoric acid is present at a concentration of 0.01 to 0.2 % w/v. Most preferably, the orthophosphoric acid is present at a concentration of about 0.05 % w/v.
  • the pH of the aqueous solution is approximately 2 to 6. More preferably the pH of the aqueous solution is approximately 2 to 4. More preferably still the pH of the aqueous solution is approximately 2 to 3. Most preferably the pH of the aqueous solution is approximately 2.3.
  • the mobile phase comprises two or more liquids, including a first liquid A and a second liquid B, wherein at least one of said liquids comprises the phosphate salt, phosphoric acid or anhydride thereof.
  • the first liquid A is the aqueous solution of the phosphate salt, phosphoric acid or anhydride thereof.
  • the second liquid B preferably comprises or is an organic solvent, such as methanol, acetonitrile, propanol or isopropanol or a mixture thereof.
  • the second liquid B comprises a polar protic solvent such as acetic acid, methanol, ethanol, n-propanol or isopropanol, and/or a dipolar aprotic solvent such as acetone, acetonitrile, dimethoxyethane, DMF, DMSO, 1,4-dioxane, pyridine, or THF.
  • a polar protic solvent such as acetic acid, methanol, ethanol, n-propanol or isopropanol
  • a dipolar aprotic solvent such as acetone, acetonitrile, dimethoxyethane, DMF, DMSO, 1,4-dioxane, pyridine, or THF.
  • the second liquid B comprises both a polar protic solvent and a dipolar aprotic solvent.
  • the polar protic solvent is not an acid.
  • the polar protic solvent is an alcohol, preferably one containing from 1 to 6 carbon atoms, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, tert-butanol or a mixture thereof. Most preferably the polar protic solvent is methanol.
  • the second liquid B comprises a dipolar aprotic solvent
  • the dipolar aprotic solvent is acetonitrile
  • the second liquid B is a mixture of acetonitrile and methanol, preferably in the ratio of 5:95 to 50:50 acetonitrile:methanol v/v, more preferably in the ratio of about 10:90 acetonitrile:methanol v/v.
  • the second liquid B is substantially water miscible.
  • Preferred embodiments of the third aspect of the current invention are when the first liquid A is an aqueous solution of orthophosphoric acid, preferably at a concentration of about 0.05 % w/v, and the second liquid B is a mixture of acetonitrile and methanol, preferably in the ratio of about 10:90 acetonitrile:methanol v/v.
  • the chromatographic method is a liquid chromatographic method such as a HPLC, LC-MS or LC-MS/MS method; preferably the chromatographic method is a HPLC method.
  • the chromatographic method may be an isocratic method, preferably such that the relative concentration of the liquids A and B by volume is set between 99.5%A : 0.5%B and 0.5%A : 99.5%B, or between 90%A : 10%B and 10%A : 90%B, more preferably between 75%A : 25%B and 25%A : 75%B. More preferably the relative concentration of the liquids A and B by volume is about 45%A : 55%B.
  • the relative concentration of the liquids in the mobile phase may be varied to a predetermined gradient.
  • the relative concentration of the liquids A and B by volume is varied to a gradient between 100 % A : 0 % B to 0 % A : 100 % B over a period of 10 to 180 minutes.
  • the gradient is between 100 % A : 0 % B to 0 % A : 100 % B over a period of 25 to 120 minutes, more preferably between 100 % A : 0 % B to 0 % A : 100 % B over a period of 25 to 60 minutes.
  • the third aspect of the current invention may comprise a gradient programming so that the relative concentration of the liquids A and B by volume is varied to a gradient starting at relative concentrations of 50-70 % A : 30-50 % B and finishing at relative concentrations of 20-40 % A : 60-80% B.
  • the gradient starts at relative concentrations of 55-65 % A : 35-45 % B and finishes at 25-35 % A : 65-75 % B.
  • the gradient starts at relative concentrations of about 60 % A : 40 % B and finishes at relative concentrations of about 30 % A : 70 % B.
  • the variation in gradient may typically take place over 10 to 180 minutes, preferably over 15 to 60 minutes, more preferably over 20 to 30 minutes.
  • a particularly preferred method according to the third aspect of the current invention is when the first liquid A is about 0.05 % w/v aqueous orthophosphoric acid and the second liquid B is a mixture of acetonitrile and methanol in the ratio of about 10:90 acetonitrile:methanol v/v and the gradient is as follows:
  • a mote preferred method according to the third aspect of the current invention is when the first liquid A is about 0.05 % w/v aqueous orthophosphoric acid and the second liquid B is a mixture of acetonitrile and methanol in the ratio of about 10:90 acetonitrile:methanol v/v and the gradient is as follows:
  • the method of the third aspect of the current invention is carried out at a column temperature between approximately 15 to 40°C.
  • a mobile phase flow rate of between 0.01 and 10 ml/min is used, more preferably a mobile phase flow rate of between 0.1 and 4 ml/min is used, more preferably a mobile phase flow rate of about 1 ml/ min is used.
  • the stationary phase used is a gel, preferably a silica gel.
  • the stationary phase used in the third aspect of the current invention is reverse phase such as octadecylsilyl silica gel, octylsilyl silica gel, phenylalkyl silica gel, cyanopropyl silica gel, aminopropyl silica gel or an alkyl-diol silica gel.
  • Particularly suitable stationary phases include octadecylsilyl silica gel or octylsilyl silica gel.
  • a particularly preferred stationary phase comprises a Cosmosil 5C 18 -MS-II (150 mm x 4.6 mm), 5 ⁇ column, preferably with a pore size of about 12 ⁇ .
  • the stationary phase has a particle size of between 0.1 and ⁇ , or between 0.5 and 25 ⁇ , or between 1 and ⁇ . More preferably the stationary phase has a particle size of about 5 ⁇ .
  • the stationary phase has a pore size of between 10 and ⁇ , or between 25 and 500A, or between 50 and 20 ⁇ . More preferably the stationary phase has a pore size of about 120A.
  • the chromatography is carried out in a column between 10mm and 5000mm in length, or in a column between 50mm and 500mm in length, or between 100mm and 250mm in length. More preferably the chromatography is carried out in a column about 150mm in length.
  • the chromatography may be carried out in a column between 0.01mm and 100mm in internal diameter, or between 0.1mm and 50mm in internal diameter, or between 1mm and 10mm in internal diameter. More preferably the chromatography is carried out in a column about 4.6mm in internal diameter.
  • the eluent may be analysed by a detector such as a UV and/ or visible spectrophotometer, a fluorescence spectrophotometer, a differential refractometer, an electrochemical detector, a mass spectrometer, a light scattering detector or a radioactivity detector.
  • N-hydroxy-N,N-di-(N'-phenyl-octanediamide) amine N-hydroxy-N,N-di-(N'-phenyl-octanediamide) amine.
  • the chromatographic method is used for the analysis of vorinostat that is suitable for use in a pharmaceutical composition.
  • the chromatographic method is used for the analysis of vorinostat that has not entered the human or animal body.
  • the vorinostat that is analysed is not in contact with a human or animal bodily fluid such as plasma.
  • the vorinostat that is analysed is not in solution.
  • d e chromatographic method is used for the analysis of a pharmaceutical composition comprising vorinostat.
  • the chromatographic method is used for the analysis of a substance comprising at least 5% vorinostat by weight.
  • the substance comprises at least 10%, at least 25%, at least 50%, at least 75% or at least 90% vorinostat by weight.
  • the substance comprises at least 95% vorinostat by weight.
  • the chromatographic method is used for the analysis of a substance comprising vorinostat as the only active pharmaceutical ingredient.
  • a fourth aspect of the current invention provides a method for analysing a substance, comprising the detection and optional quantification of one or more impurities selected from:
  • the method comprises the detection and optional quantification of two or more of the above impurities. Most preferably, the method comprises the detection and optional quantification of all four of the above impurities.
  • the substance is an active pharmaceutical ingredient.
  • the substance is or comprises vorinostat.
  • the substance may comprise at least 5% vorinostat by weight.
  • the substance comprises at least 10%, at least 25%, at least 50%, at least 75% or at least 90% vorinostat by weight.
  • the substance comprises at least 95% vorinostat by weight.
  • the vorinostat is suitable for use in a pharmaceutical composition.
  • the substance comprises less than 25 wt.% of the one or more impurities.
  • the substance comprises less dian 10 wt.%, less than 5 wt.% or less than 2 wt.% of the one or more impurities. More preferably die substance comprises less than 1 wt.%, or less than 0.5 wt.% of the one or more impurities.
  • the substance comprises vorinostat as the only active pharmaceutical ingredient.
  • the substance is a pharmaceutical composition comprising vorinostat.
  • the substance that is analysed has not entered the human or animal body.
  • the substance that is analysed is not in contact with a human or animal bodily fluid such as plasma.
  • the substance that is analysed is not in solution.
  • the method is a chromatographic method.
  • the chromatographic method is a liquid chromatographic method such as a HPLC, LC-MS or LC-MS/MS method.
  • the chromatographic method is a HPLC method.
  • the method according to the fourth aspect of the current invention is a chromatographic method
  • the detection and optional quantification of d e impurities takes place in a single run and/ or using a single column.
  • the mobile phase used in the chromatographic method comprises two or more liquids, including a first liquid A and a second liquid B.
  • the first liquid A is aqueous based, such as water or an aqueous solution of a buffer.
  • the buffer is an acid or an organic salt or an inorganic salt or a mixture thereof.
  • the buffer is a phosphate salt, an acetate salt, a trifluoroacetate salt, a formate salt, acetic acid, trifluoroacetic acid, formic acid, a phosphoric acid or a mixture thereof. More typically, the buffer is a phosphate salt, an acetate salt, a formate salt, acetic acid, trifluoroacetic acid, orthophosphoric acid or a mixture thereof.
  • the buffer is a phosphate salt, a phosphoric acid or an anhydride thereof, such as orthophosphoric acid, pyrophosphoric acid, tripolyphosphoric acid, tetrapolyphosphoric acid, trimetaphosphoric acid or phosphoric anhydride.
  • die buffer is an acid, such as orthophosphoric acid.
  • the buffer can be present at a concentration of 0.001 to 0.2 % w/v, preferably at a concentration of 0.005 to 0.1 % w/v, more preferably at a concentration of 0.01 to 0.1 % w/v, most preferably at a concentration of about 0.05 % w/v.
  • the buffer is orthophosphoric acid at a concentration of 0.01 to 0.2 % w/v. Most preferably, the buffer is orthophosphoric acid present at a concentration of about 0.05 % w/v.
  • die pH of the buffer solution is approximately 2 to 6. More preferably the pH of the buffer solution is approximately 2 to 4. More preferably still the pH of the buffer solution is approximately 2 to 3. Most preferably the pH of the buffer solution is approximately 2.3.
  • the second liquid B preferably comprises or is an organic solvent, such as methanol, acetonitrile, propanol or isopropanol or a mixture thereof.
  • the second liquid B comprises a polar protic solvent such as acetic acid, methanol, ethanol, n-propanol or isopropanol, and/or a dipolar aprotic solvent such as acetone, acetonitrile, dimethoxyethane, DMF, DMSO, 1,4-dioxane, pyridine, or THF.
  • a polar protic solvent such as acetic acid, methanol, ethanol, n-propanol or isopropanol
  • a dipolar aprotic solvent such as acetone, acetonitrile, dimethoxyethane, DMF, DMSO, 1,4-dioxane, pyridine, or THF.
  • the second liquid B comprises both a polar protic solvent and a dipolar aprotic solvent.
  • the second liquid B comprises a polar protic solvent
  • the polar protic solvent is not an acid.
  • the polar protic solvent is an alcohol, preferably one containing from 1 to 6 carbon atoms, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, tert-butanol or a mixture thereof.
  • the polar protic solvent is methanol.
  • the second liquid B comprises a dipolar aprotic solvent
  • the dipolar aprotic solvent is acetonitrile.
  • the second liquid B is a mixture of acetonitrile and methanol, preferably in the ratio of 5:95 to 50:50 acetonitrile:methanol v/v, more preferably in the ratio of about 10:90 acetonitrile:methanol v/v.
  • the second liquid B is substantially water miscible.
  • Preferred embodiments of the fourth aspect of the current invention are when the first liquid A is an aqueous solution of orthophosphoric acid, preferably at a concentration of about 0.05 % w/v, and the second liquid B is a mixture of acetonitrile and methanol, preferably in the ratio of about 10:90 acetonitrile:methanol v/v.
  • the chromatographic method may be an isocratic method, preferably such that the relative concentration of the liquids A and B by volume is set between 99.5%A : 0.5%B and 0.5%A : 99.5%B, or between 90%A : 10%B and 10%A : 90%B, more preferably between 75%A : 25%B and 25%A : 75%B. More preferably the relative concentration of the liquids A and B by volume is about 45%A : 55%B.
  • the relative concentration of the liquids in the mobile phase may be varied to a predetermined gradient.
  • the relative concentration of the liquids A and B by volume is varied to a gradient between 100 % A : 0 % B to 0 % A : 100 % B over a period of 10 to 180 minutes.
  • the gradient is between 100 % A : 0 % B to 0 % A : 100 % B over a period of 25 to 120 minutes, more preferably between 00 % A : 0 % B to 0 % A : 100 % B over a period of 25 to 60 minutes.
  • the fourth aspect of the current invention may comprise a gradient programming so that the relative concentration of the liquids A and B by volume is varied to a gradient starting at relative concentrations of 50-70 % A : 30-50 % B and finishing at relative concentrations of 20-40 % A : 60-80% B.
  • the gradient starts at relative concentrations of 55-65 % A : 35-45 % B and finishes at 25-35 % A : 65-75 % B.
  • the gradient starts at relative concentrations of about 60 % A : 40 % B and finishes at relative concentrations of about 30 % A : 70 % B.
  • the variation in gradient may typically take place over 10 to 180 minutes, preferably over 15 to 60 minutes, more preferably over 20 to 30 minutes.
  • a particularly preferred chromatographic method according to the fourth aspect of the current invention is when the first liquid A is about 0.05 % w/v aqueous orthophosphoric acid and the second liquid B is a mixture of acetonitrile and methanol in the ratio of about 10:90 acetonitrile:methanol v/v and the gradient is as follows:
  • a more preferred chromatographic method according to the fourth aspect of the current invention is when the first liquid A is about 0.05 % w/v aqueous orthophosphoric acid and the second liquid B is a mixture of acetonitrile and methanol in the ratio of about 10:90 acetonitrile:methanol v/v and the gradient is as follows:
  • the chromatographic method of the fourth aspect of the current invention is carried out at a column temperature between approximately 15 to 40°C.
  • a mobile phase flow rate of between 0.01 and 10 n l/min is used, more preferably a mobile phase flow rate of between 0.1 and 4 ml/min is used, more preferably a mobile phase flow rate of about 1 ml/ min is used.
  • the stationary phase used in the chromatographic method is a gel, preferably a silica gel.
  • the stationary phase used in the fourth aspect of the current invention is reverse phase such as octadecylsilyl silica gel, octylsilyl silica gel, phenylalkyl silica gel, cyanopropyl silica gel, aminopropyl silica gel or an alkyl-diol silica gel.
  • Particularly suitable stationary phases include octadecylsilyl silica gel or octylsilyl silica gel.
  • a particularly preferred stationary phase comprises a Cosmosil 5C 18 -MS-II (150 mm x 4.6 mm), 5 ⁇ column, preferably with a pore size of about 120A.
  • the stationary phase has a particle size of between 0.1 and ⁇ , or between 0.5 and 25 ⁇ , or between 1 and ⁇ . More preferably the stationary phase has a particle size of about 5 ⁇ .
  • the stationary phase has a pore size of between 10 and ⁇ , or between 25 and 500A, or between 50 and 20 ⁇ . More preferably the stationary phase has a pore size of about 120A.
  • the chromatography is carried out in a column between 10mm and 5000mm in length, or in a column between 50mm and 500mm in length, or between 100mm and 250mm in length. More preferably the chromatography is carried out in a column about 150mm in length.
  • the chromatography may be carried out in a column between 0.01mm and 100mm in internal diameter, or between 0.1mm and 50mm in internal diameter, or between 1mm and 10mm in internal diameter. More preferably the chromatography is carried out in a column about 4.6mm in internal diameter.
  • the eluent may be analysed by a detector such as a UV and/ or visible spectrophotometer, a fluorescence spectrophotometer, a differential refractometer, an electrochemical detector, a mass spectrometer, a light scattering detector or a radioactivity detector.
  • a detector such as a UV and/ or visible spectrophotometer, a fluorescence spectrophotometer, a differential refractometer, an electrochemical detector, a mass spectrometer, a light scattering detector or a radioactivity detector.
  • one or more of the following compounds are used as internal or external reference marker(s) or as internal or external reference standard(s): 1) ⁇ , ⁇ '-diphenyl-octanediamide
  • a fifth aspect of the current invention provides the use of any of:
  • the reference marker or reference standard is used in a chromatographic method.
  • the reference marker or reference standard may be used as an internal reference marker or reference standard.
  • the reference marker or reference standard may be used as an external reference marker or reference standard.
  • the reference marker or reference standard is used in a method of testing die purity of vorinostat or of a pharmaceutical composition comprising vorinostat.
  • the reference marker or reference standard is used in a method according to any of the first to fourth aspects of the current invention.
  • a sixth aspect of the current invention provides vorinostat which has been subjected to a method according to any of the first to fourth aspects of the current invention.
  • the vorinostat is substantially free of one, two, three or all four of:
  • a seventh aspect of the current invention provides vorinostat which is substantially free of one, two, three or all four of:
  • Vorinostat is "substantially free” of a compound, if it comprises less than about 5% of that compound, preferably less than about 3%, preferably less than about 2%, preferably less than about 1%, preferably less than about 0.5%, preferably less than about 0.1%, preferably less than about 0.05%, preferably as measured by HPLC.
  • An eighth aspect of the current invention provides a pharmaceutical composition comprising vorinostat according to the sixth or seventh aspects of the current invention.
  • the pharmaceutical composition comprises one or more pharmaceutically acceptable excipients.
  • a ninth aspect of the current invention provides N'-phenyl-octanediamide or a salt, tautomer, solvate or hydrate thereof.
  • a tenth aspect of the current invention provides N-hydroxy-N,N-di-(N'-phenyl- octanediamide) amine or a salt, tautomer, solvate or hydrate thereof.
  • any embodiment of a given aspect of the current invention may occur in combination with any other embodiment of the same aspect of the current invention.
  • any preferred or optional embodiment of any aspect of the current invention should also be considered as a preferred or optional embodiment of any other aspect of the current invention.
  • the current invention can be used to analyse vorinostat and/or its salts as an API or vorinostat and/ or its salts when prepared as a pharmaceutical composition.
  • compositions that can be analysed by the current invention include solid and liquid compositions and optionally comprise one or more pharmaceutically acceptable carriers or excipients.
  • Solid form compositions include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
  • Liquid compositions include solutions or suspensions which can be administered by oral, injectable or infusion routes.
  • impurities or related substances as used herein throughout the specification can mean either impurities formed in the manufacture of the API or the pharmaceutical composition and/or formed by degradation of the API or in the pharmaceutical composition on storage.
  • the HPLC methods reported in the prior art are not suitable for analysing vorinostat, particularly with respect to the related substances formed in the synthesis of vorinostat and/or its salts prepared by the process disclosed in co-pending patent application WO 2010/043904.
  • the current invention solves this problem and efficiently detects and quantifies, in a single run, all impurities and intermediates formed in the synthetic process.
  • the current invention is advantageous as the gradient method allows the elution of all polar to non- polar impurities.
  • the current invention is also advantageous as the method is selective, linear and precise for the analysis of related substances in vorinostat and/or its salts.
  • the current invention is highly sensitive and allows detection and quantification of related substances in vorinostat and/ or its salts at levels much lower than acceptance limits typically specified by health authorities.
  • the method of the current invention can be used to easily detect and quantify all degradation impurities formed on storage of samples of vorinostat. This was established by carrying out forced degradation studies as per ICH Q1A (R2) Guidelines and validated as per ICH Q2C (Rl) Guidelines covering the parameters Specificity, Linearity and Range, Precision (Repeatability, Reproducibility and Intermediate Precision), Limit of Detection (LOD), Limit of Quantitation (LOQ) and System Suitability.
  • the buffer optionally used in the first liquid A can be an inorganic salt such as sodium, potassium, calcium, magnesium, lithium or aluminium salts of phosphate, acetate or formate or an acid such as orthophosphoric acid, trifiuoiOacetic acid, acetic acid, formic acid or mixtures thereof.
  • the buffer can be an organic salt such as the ammonium salt of acetate or formate and mixtures thereof.
  • the buffer is an acid such as orthophosphoric acid, acetic acid or trifluoroacetic acid.
  • the first liquid A is an aqueous orthophosphoric acid solution.
  • the second liquid B can be an organic solvent like a C r C 6 alkyl alcohol, such as methanol, ethanol, propanol, butanol or isopropanol or mixtures thereof.
  • the organic solvent(s) may be tetrahydrofuran, ethyl acetate or acetonitrile or other suitable organic solvent(s).
  • the organic solvent is a mixture of acetonitrile and methanol.
  • the stationary phase used in the method of the current invention is selected from octadecylsilyl silica gel (RP-18) or octylsilyl silica gel (RP-8).
  • An internal standard reference compound may be used in the method of the current invention if required.
  • the concentration of the components analysed may be determined by comparison with one or mote external reference compounds.
  • the inventors have tested the methods of the current invention extensively to show that they are reproducible, precise and linear with respect to concentration.
  • Diluent 0.05 % w/v orthophosphoric acid - methanol (50:50 v/v); the diluent is used to dissolve the samples and inject them into the column; the column is then run using the mobile phase outlined below;
  • First liquid A aqueous 0.05 % w/v orthophosphoric acid
  • Second liquid B acetonitrile - methanol (10:90 v/v);
  • RT Retention times
  • RRT Relative retention times
  • LOD Limit of Detection
  • LOQ Limit of Quantitation

Abstract

La présente invention porte sur de nouveaux procédés HPLC pour l'analyse de la substance médicamenteuse vorinostat et de substances apparentées. Dans un premier procédé, la phase mobile comprend deux ou plus de deux liquides et la concentration relative des liquides est amenée à varier selon un gradient prédéfini. Dans un deuxième procédé, la phase mobile comprend un alcool. Dans un troisième procédé, la phase mobile comprend un sel phosphate, un acide phosphorique ou un anhydride de celui-ci. La présente invention porte également sur un procédé d'analyse d'une substance, comprenant la détection et la quantification éventuelle d'une ou de plusieurs impuretés spécifiques. La présente invention porte en outre sur l'utilisation de substances spécifiques comme étalons de référence et marqueurs et sur du vorinostat et des compositions pharmaceutiques associées qui ont été analysés par les procédés de la présente invention et/ou qui sont pratiquement exempts d'impuretés spécifiques.
PCT/GB2010/051931 2009-11-23 2010-11-20 Procédé hplc pour l'analyse de vorinostat WO2011061545A1 (fr)

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CN103018347A (zh) * 2011-09-21 2013-04-03 北京本草天源药物研究院 伏立诺他及其药物组合物中的杂质的高效液相色谱分析方法
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CN105259261A (zh) * 2015-10-09 2016-01-20 扬子江药业集团江苏海慈生物药业有限公司 一种药物中苯胺含量的测定方法
CN105510488A (zh) * 2016-01-25 2016-04-20 亚宝药业集团股份有限公司 一种止痛贴剂的指纹图谱及其质量检测方法
WO2020067680A1 (fr) * 2018-09-27 2020-04-02 주식회사 엘지화학 Procédé d'analyse de dianhydride
CN111426773A (zh) * 2020-05-27 2020-07-17 上海旭东海普药业有限公司 高效液相色谱法检测盐酸胺碘酮中的碘化物杂质
US11639917B2 (en) 2018-09-27 2023-05-02 Lg Chem, Ltd. Dianhydride analysis method

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8754129B2 (en) 2008-11-26 2014-06-17 Generics [Uk] Limited Crystalline vorinostat form VI
CN103018346A (zh) * 2011-09-20 2013-04-03 北京本草天源药物研究院 伏立诺他及其药物组合物中的杂质的高效液相色谱分析方法
CN103018347A (zh) * 2011-09-21 2013-04-03 北京本草天源药物研究院 伏立诺他及其药物组合物中的杂质的高效液相色谱分析方法
CN105259261A (zh) * 2015-10-09 2016-01-20 扬子江药业集团江苏海慈生物药业有限公司 一种药物中苯胺含量的测定方法
CN105510488A (zh) * 2016-01-25 2016-04-20 亚宝药业集团股份有限公司 一种止痛贴剂的指纹图谱及其质量检测方法
WO2020067680A1 (fr) * 2018-09-27 2020-04-02 주식회사 엘지화학 Procédé d'analyse de dianhydride
US11639917B2 (en) 2018-09-27 2023-05-02 Lg Chem, Ltd. Dianhydride analysis method
CN111426773A (zh) * 2020-05-27 2020-07-17 上海旭东海普药业有限公司 高效液相色谱法检测盐酸胺碘酮中的碘化物杂质
CN111426773B (zh) * 2020-05-27 2023-04-07 上海旭东海普药业有限公司 高效液相色谱法检测盐酸胺碘酮中的碘化物杂质

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