WO2011095803A1 - Méthode hplc pour l'analyse de frovatriptan - Google Patents

Méthode hplc pour l'analyse de frovatriptan Download PDF

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Publication number
WO2011095803A1
WO2011095803A1 PCT/GB2011/050168 GB2011050168W WO2011095803A1 WO 2011095803 A1 WO2011095803 A1 WO 2011095803A1 GB 2011050168 W GB2011050168 W GB 2011050168W WO 2011095803 A1 WO2011095803 A1 WO 2011095803A1
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WIPO (PCT)
Prior art keywords
salt
frovatriptan
present
hplc method
concentration
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PCT/GB2011/050168
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English (en)
Inventor
Erra Koteswara Satya Vijayakumar
Vinayak Vele
Sandesh Parab
Avinash Nikam
Maitreyee Samel
Original Assignee
Generics [Uk] Limited
Mylan India Private Limited
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Application filed by Generics [Uk] Limited, Mylan India Private Limited filed Critical Generics [Uk] Limited
Publication of WO2011095803A1 publication Critical patent/WO2011095803A1/fr

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    • 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
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C07D209/88—Carbazoles; Hydrogenated carbazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system

Definitions

  • the present invention relates to a new HPLC method for the analysis of the drug substance frovatriptan and related substances.
  • the present invention relates to a new HPLC method for the analysis of the drug substance frovatriptan monosuccinate monohydrate and related substances.
  • the mobile phase comprises two or more liquids and the relative concentration of die liquids is varied to a predetermined gradient.
  • the stationary phase is reverse phase and the mobile phase comprises an alcohol and/or an aUtylamine.
  • the mobile phase comprises a formate salt.
  • a final method comprises the detection and optional quantification of specific impurities.
  • the present invention also relates to frovatriptan and associated pharmaceutical compositions from which samples have been analysed by the methods of die invention and/ or which are substantially free of specific impurities.
  • API active pharmaceutical ingredient
  • the likely impurities in APIs and pharmaceutical compositions include residual quantities of synthetic precursors (intermediates), by-products which arise during synthesis of the API, residual solvents, isomers of the API (e.g. geometrical isomers, diastereomers or enantiomers), contaminants which ate 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 ate 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 the API or pharmaceutical compositions are safe and effective include purity assay, related substances, content uniformity and dissolution tests.
  • the purity assay 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 Mice 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.
  • 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.
  • 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 malting 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. If 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 with the stationary phase as strongly 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.
  • Frovatriptan chemically known as (+)-R-3-methykmino-6-carboxamido-l, 2,3,4- tetrahydrocarbazole, is an orally active 5-hydroxytriptamine (5-HT) receptor agonist and is used for the management of migraine symptoms.
  • Frovatriptan is marketed as its monosuccinate monohydrate salt (I) (commonly referred to as frovatriptan succinate monohydrate) with the brand name Frova ® .
  • HPLC methods reported in the prior art are not particularly convenient or suitable for analysing frovatriptan API, particularly with respect to related substances.
  • an object of the present invention to provide a new, accurate and sensitive HPLC method for the detection and quantitation of all intermediates and related substances that are formed and may remain in the batches of frovatriptan whilst avoiding the typical problems associated with the prior art methods.
  • a particular object of the invention is to provide a new, accurate and sensitive HPLC method for the detection and quantitation of all intermediates and related substances that are formed and may remain in the batches of frovatriptan synthesized by the process disclosed in co-pending Indian patent application IN 657/KOL/2009 and the corresponding international patent application WO 2010/122343.
  • frovatriptan as used herein throughout the description and claims means frovatriptan and/or any salt, solvate, hydrate, anhydrate, tautomer, isomer or enantiomer thereof.
  • the present invention is particularly useful for the analysis of frovatriptan monosuccinate monohydrate.
  • a first aspect of the present invention provides a HPLC method for analysing frovatriptan or a salt thereof, wherein the mobile phase comprises two or more Hquids and the relative concentration of the liquids is varied to a predetermined gradient.
  • 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 selected from an acid, an organic salt, an inorganic salt, an organic base (such as a c aUcylamine or a triaUiylamine) or a mixture thereof.
  • the buffer is a phosphate salt, an acetate salt, a formate salt, a trifluoroacetate salt, a phosphoric acid, acetic acid, formic acid, trifluoroacetic acid, an aU ⁇ lamine such as cHemylamine, n-propylamine or ttiemylamine, or a mixture thereof. More typically, the buffer is a phosphate salt, an acetate salt, a formate salt, acetic acid, trifluoroacetic acid, diemylamine, n-propylamine, ttiemylamine or a mixture thereof.
  • an "alkyl” group is defined as a monovalent saturated hydrocarbon, which may be straight-chained or branched, or be or include cyclic groups.
  • An alkyl group may optionally include one or more heteroatoms N, O or S in its carbon skeleton.
  • Examples of alkyl groups are methyl, ethyl, /?-propyl, z-propyl, »-butyl, i- butyl, /-butyl and /z-pentyl groups.
  • an alkyl group is straight-chained or branched and does not include any heteroatoms in its carbon skeleton.
  • an alkyl group is a C r C 12 alkyl group, which is defined as an alkyl group containing from 1 to 12 carbon atoms. More preferably an alkyl group is a C C 6 alkyl group, which is defined as an alkyl group containing from 1 to 6 carbon atoms.
  • the buffer comprises a carboxylate salt and/ or an organic base.
  • the carboxylate salt is an acetate salt, a formate salt or a trifluoroacetate salt. More preferably the carboxylate salt is a formate salt such as ammonium formate.
  • the organic base is an amine such as an alkylamine.
  • the alkylamine may be selected from a monoalkylamine such as emylamine, n-propylamine or isopropylamine, a dialkylamine such as diemylamine, N-etiiyl-N-methylamine or N- emyl-N-n-propylamine, a cycKc-alkylamine such as piperidine, pyrrolidine or morpholine, or a tiialfylamine such as toe ylamine, dnsopropylemylamine or dimemylemylamine.
  • the all ⁇ amine is a monoalkylamine such as emylamine, n-propylarnine or isopropylamine. More preferably the alfylamine is n-propylamine.
  • an ' ⁇ U ⁇ lamine preferably contains from 1 to 20 carbon atoms, more preferably contains from 2 to 12 carbon atoms and most preferably contains from 3 to 8 carbon atoms.
  • the buffer is or comprises a salt
  • the counter cation is an ammonium cation
  • the buffer is a mixture of a formate salt, such as ammonium formate, and a base, more preferably an organic base, such as n-propylamine.
  • a formate salt such as ammonium formate
  • a base more preferably an organic base, such as n-propylamine.
  • the salt in the buffer can be present at a concentration of 0.001 to 0.2 M, preferably at a concentration of 0.005 to 0.1 M, more preferably at a concentration of 0.01 to 0.1 M, and most preferably at a concentration of about 0.02 M; and/ or the base in the buffer can be present at a concentration of 0.001 to 0.2 % v/v, preferably at a concentration of 0.005 to 0.2 % v/v, more preferably at a concentration of 0.01 to 0.2 % v/v, and most preferably at a concentration of about 0.05 % v/v.
  • the buffer is a mixture of ammonium formate present at a concentration of 0.01 to 0.1 M and n-propylamine at a concentration of 0.01 % to 0.2 % v/v.
  • the buffer is a mixture of ammonium formate present at a concentration of about 0.02 M and n-propylamine at a concentration of about 0.1 % v/v.
  • the pH of the buffer solution is approximately 7.5 to 10. More preferably the pH of the buffer solution is approximately 8.5 to 9.5. Most preferably the pH of the buffer- solution is approximately 9.2.
  • the method of the first aspect of the present invention is carried out at a column temperature between approximately 15 to 40°C.
  • the mobile phase can comprise a second liquid B which is or comprises an organic solvent, preferably selected from an alcohol, preferably an alkyl alcohol, such as methanol, ethanol, propanol or iso-propanol, or acetonitrile, or a mixture thereof.
  • the second liquid B comprises or is a polar protic organic solvent such as acetic acid, methanol, ethanol, n- propanol, n-butanol, iso-propanol, iso-butanol, sec-butanol or tert-butanol, or a mixture thereof.
  • polar protic organic solvent is an alcohol such as a C r C 6 alcohol. More preferably the alcohol is an alkyl alcohol.
  • the alcohol is a C r C 4 alkyl alcohol such as methanol, ethanol, n-propanol, n-butanol, iso-propanol, iso-butanol, sec-butanol or tert-butanol.
  • the second liquid B is methanol.
  • the second liquid B is substantially water miscible.
  • X and Y may form a single phase where the mole fraction of Y, x Y , is from 0.40 to 0.45, or from 0.70 to 0.75; in both cases ⁇ ⁇ — 0.05.
  • 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.
  • the mobile phase contains less than 10%, less than 5% or less than 1% acetonitrile by volume. In one embodiment, the mobile phase contains no acetonitrile.
  • the mobile phase contains less than 10%, less than 5% or less than 1 % of any organic dipolar aprotic solvent by volume. In one embodiment, the mobile phase contains no organic dipolar aprotic solvent.
  • a preferred embodiment of the first aspect of the present invention is when the first liquid A is an aqueous solution of a buffer comprising a formate salt mixed with n-propylamine, and the second liquid B is methanol.
  • a particularly preferred embodiment of the first aspect of the present invention is when the first liquid A is 0.02 M ammonium formate containing 0.1 % v/v n-propylamine and the second liquid B is methanol.
  • the method of the first aspect of the present invention preferably 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 30 to 120 minutes, more preferably 100 % A : 0 % B to 0 % A : 100 % B over a period of 30 to 70 minutes.
  • the HPLC method of the first aspect of the present invention may comprise a gradient programming so that the relative concentration of the liquids A and B by volume starts at a first ratio, then is varied to a first gradient over a first period of time, to arrive at a second ratio.
  • the first ratio may be 65-85 % A ; 15-35 % B.
  • die first ratio is 70-80 % A : 20- 30 % B.
  • the first ratio is about 75 % A : 25 % B.
  • the first period of time may be from 0 to 120 minutes. Preferably the first period of time is from 30 to 90 minutes. Most preferably the first period of time is about 50 minutes.
  • the second ratio may be 10-30 % A : 70-90 % B. Preferably the second ratio is 15-25 % A : 75-85 % B. Most preferably the second ratio is about 20 % A : 80 % B.
  • 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 still a mobile phase flow rate of between 0.5 and 1.5 ml/min is used, most 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 is chiral and/or the mobile phase further comprises a chiral selector. In other embodiments however the stationary phase used is non-chiral.
  • the stationary phase used in the first aspect of the present 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 Waters XTerra RP18 (250 mm x 4.6 mm), 5 ⁇ column.
  • the stationary phase has a particle size of between 0.1 and ⁇ , or between 0.5 and 25 ⁇ , or between 1 and ⁇ , or between 4.5 and 6 ⁇ . 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 between 100 and 175A, or between 125 and 15 ⁇ . Most preferably the stationary phase has a pore size or about 137A.
  • the chromatography is carried out in a column between 10mm and 5000mm in length, or in a column between 50mm and 1000mm in length, or between 100mm and 500mm in lengtli. More preferably the chromatography is carried out in a column between 200mm and 280mm in length. Most preferably the chromatography is carried out in a column about 250mm 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 present invention is when the first liquid A is 0.02 M ammonium formate containing 0.1 % v/v n-propylamine and the second liquid B is methanol 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 detects and optionally quantifies in a single run one or more impurities selected from:
  • (+)-3-N-benzyl-6-carboxamido-3-N-memylarrimo-l,2,3,4-tetrahydiOcarbazole (+)-3-Arrimo-6-carboxamido-l,2,3,4-tetrahydrocarbazole has the structure of compound (VII) in Scheme 7 on page 17 of WO 2010/122343, whilst (+)-3-N-benzyl-6-carboxamido- 3-N-memylamino-l,2,3,4-tetrahydrocarbazole has the structure of compound (VIII) in the same scheme.
  • the HPLC method detects and optionally quantifies in a single run both (+)-3- amino-6-carboxamido-l ,2,3,4-tetrahydrocarbazole and (+)-3-N-benzyl-6-carboxamido-3- N-memylamino-l,2,3,4-tetrahydrocarbazole.
  • the HPLC method according to the first aspect of the present invention efficiently detects and quantifies in a single run all impurities including those selected from the following compounds:
  • (+)-3-amino-6- carboxamido-l,2,3,4-tetrahydrocarbazole and/ or (+)-3-N-benzyl-6-carboxamido-3-N- methylamino-l,2,3,4-tetrahydrocarbazole is used as internal or external reference marker, or as internal or external reference standard.
  • frovatriptan and/ or R- 3-emylamino-6-carboxamido-l,2,3,4-tetrahydrocarbazole is used as internal or external reference marker, or as internal or external reference standard.
  • the method of the first aspect of the present invention is for analysing frovatriptan monosuccinate. More preferably the method of the first aspect of the present invention is for analysing frovatriptan monosuccinate monohydrate.
  • the HPLC method is used for the analysis of frovatriptan or a salt thereof that is suitable for use in a pharmaceutical composition.
  • the HPLC method is used for the analysis of frovatriptan or a salt thereof that has not entered the human or animal body.
  • the frovatriptan or the salt thereof that is analysed is not in contact with a human or animal bodily fluid such as whole blood or plasma.
  • the frovatriptan or the salt thereof that is analysed is not in solution.
  • the HPLC method is used for the analysis of a pharmaceutical composition comprising frovatriptan or a salt thereof.
  • the HPLC method is used for the analysis of a substance comprising at least 5% frovatriptan or a salt thereof by weight.
  • the substance comprises at least 10%, at least 25%, at least 50%, at least 75% or at least 90% frovatriptan or a salt thereof by weight.
  • the substance comprises at least 95% frovatriptan or a salt thereof by weight.
  • the HPLC method is used for the analysis of a substance comprising frovatriptan or a salt thereof as the only active pharmaceutical ingredient.
  • a second aspect of the present invention provides a chromatographic method for analysing frovatriptan or a salt thereof, wherein the stationary phase is reverse phase and the mobile phase comprises an alcohol.
  • the alcohol is substantially water miscible.
  • the alcohol is a C 1 -C 6 alcohol.
  • the alcohol is an alkyl alcohol. More preferably the alcohol is a C r C 4 alkyl alcohol such as methanol, ethanol, n-propanol, n-butanol, iso-propanol, iso-butanol, sec-butanol or tert-butanol. 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 second liquid B is the alcohol.
  • the first liquid A is aqueous based, such as water or an aqueous solution of a buffer.
  • the buffer is selected from an acid, an organic salt, an inorganic salt, an organic base (such as a diaUtylamine or a trialliylamine) or a mixture thereof.
  • the buffer is a phosphate salt, an acetate salt, a formate salt, a trifluoroacetate salt, a phosphoric acid, acetic acid, formic acid, trifluoroacetic acid, an alfylarnine such as diethylamine, n-propylamine or triethylamine, or a mixture thereof.
  • the buffer is a phosphate salt, an acetate salt, a formate salt, acetic acid, trifluoroacetic acid, diethylamine, n-propylamine, triethylamine or a mixture thereof.
  • the buffer comprises a carboxylate salt and/ or an organic base.
  • the carboxylate salt is an acetate salt, a formate salt or a trifluoroacetate salt. More preferably the carboxylate salt is a formate salt such as ammonium formate.
  • the organic base is an amine such as an aUcylamine.
  • the aUtylamine may be selected from a monoalliylamine such as ethylamine, n-propylamine or isopropylamine, a cualkylamine such as ckethylamine, N-eAyl-N-memylamine or N- ethyl-N -n-propylamine, a cyclic-alkylamine such as piperidine, pyrrolidine or morpholine, or a ttiaU ⁇ lamine such as triethylamine, dusopropyletJiylamine or dimelitylethylamine.
  • a monoalliylamine such as ethylamine, n-propylamine or isopropylamine
  • a cualkylamine such as ckethylamine, N-eAyl-N-memylamine or N- ethyl-N -n-propylamine
  • a cyclic-alkylamine
  • the aUiylamine is a monoalkylamine such as ethylamine, n-propylamine or isopropylamine. More preferably the alfylamine is n-propylamine.
  • the buffer is or comprises a salt, preferably the counter cation is an ammonium cation.
  • the buffer is a mixture of a formate salt, such as ammonium formate, and a base, more preferably an organic base, such as n-propylamine.
  • a formate salt such as ammonium formate
  • a base more preferably an organic base, such as n-propylamine.
  • the salt in the buffer can be present at a concentration of 0.001 to 0.2 M, preferably at a concentration of 0.005 to 0.1 M, more preferably at a concentration of 0.01 to 0.1 M, and most preferably at a concentration of about 0.02 M; and/ or the base in die buffer can be present at a concentration of 0.001 to 0.2 % v/v, preferably at a concentration of 0.005 to 0.2 % v/v, more preferably at a concentration of 0.01 to 0.2 % v/v, and most preferably at a concentration of about 0.05 % v/v.
  • the buffer is a mixture of ammonium formate present at a concentration of 0.01 to 0.1 M and n-propylamine at a concentration of 0.01 % to 0.2 % v/v. Most preferably the buffer is a mixture of ammonium formate present at a concentration of about 0.02 M and n-propylamine at a concentration of about 0.1 % v/v.
  • the pH of the buffer solution is approximately 7.5 to 10. More preferably the pH of the buffer solution is approximately 8.5 to 9.5. Most preferably the pH of the buffer solution is approximately 9.2.
  • the mobile phase contains less than 10%, less than 5% or less than 1% acetonittile by volume. In one embodiment, the mobile phase contains no acetonitrile.
  • the mobile phase contains less than 10%, less than 5% or less than 1% of any organic dipolar aprotic solvent by volume. In one embodiment, the mobile phase contains no organic dipolar aprotic solvent.
  • a preferred embodiment of the second aspect of the present invention is when the first liquid A is an aqueous solution of a buffer comprising a formate salt mixed with n- propylamine, and the second liquid B is methanol.
  • a particularly preferred embodiment of the second aspect of the present invention is when the first liquid A is 0.02 M ammonium formate containing 0.1 % v/v n-propylamine and the second liquid B is methanol.
  • 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 still the relative concentration of the liquids A and B by volume is about 50 % A : 50 % 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 30 to 120 minutes, more preferably 100 % A : 0 % B to 0 % A : 100 % B over a period of 30 to 70 minutes.
  • the chromatographic method of the second aspect of the present invention may comprise a gradient programming so that the relative concentration of the liquids A and B by volume starts at a first ratio, then is varied to a first gradient over a first period of time, to arrive at a second ratio.
  • the first ratio may be 65-85 % A : 15-35 % B. Preferably the first ratio is 70-80 % A : 20- 30 % B. Most preferably the first ratio is about 75 % A : 25 % B.
  • the first period of time may be from 0 to 120 minutes. Preferably the first period of time is from 30 to 90 minutes. Most preferably the first period of time is about 50 minutes.
  • the second ratio may be 10-30 % A : 70-90 % B. Preferably the second ratio is 15-25 % A : 75-85 % B. Most preferably the second ratio is about 20 % A : 80 % B.
  • a particularly preferred method according to the second aspect of the present invention is when the first liquid A is 0.02 M ammonium formate containing 0.1 % v/v n-propylamine and the second liquid B is methanol and the gradient is as follows:
  • the method of the second aspect of the present 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 still a mobile phase flow rate of between 0.5 and 1.5 ml/min is used, most preferably a mobile phase flow rate of about 1 ml/ min is used.
  • the reverse phase stationary phase used is a gel, preferably a silica gel.
  • the stationary phase used is chiral and/or the mobile phase further comprises a chiral selector. In other embodiments however the stationary phase used is non-chiral.
  • the reverse phase stationary phase used in the second aspect of the present invention is selected from an octadecylsilyl silica gel, an octylsilyl silica gel, a phenylalkyl silica gel, a cyanopropyl silica gel, an 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 Waters XTerra RP18 (250 mm x 4.6 mm), 5 ⁇ column.
  • the stationary phase has a particle size of between 0.1 and ⁇ , or between 0.5 and 25 ⁇ , or between 1 and ⁇ , or between 4.5 and 6 ⁇ . 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 200A. More preferably the stationary phase has a pore size of between 100 and 175A, or between 125 and 15 ⁇ . Most preferably the stationary phase has a pore size of about 137A.
  • the chromatography is carried out in a column between 10mm and 5000mm in length, or in a column between 50mm and 1000mm in length, or between 100mm and 500mm in length. More preferably the chromatography is carried out in a column between 200mm and 280mm in length. Most preferably the chromatography is carried out in a column about 250mm 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.
  • the chromatographic method detects and optionally quantifies in a single run both (+)-3-ammo-6-carboxamido-l,2,3,4-tetrahydrocarbazole and (+)-3-N-benzyl-6- carboxamido-3-N-memykrnino-l,2,3,4-tetrahydrocarbazole.
  • (+)-3-amino-6- carboxamido-l,2,3,4-tetrahydrocarbazole and/ or (+)-3-N-benzyl-6-carboxamido-3-N- memylamino-l,2,3,4-tetrahydrocarbazole is used as internal or external reference marker, or as internal or external reference standard.
  • frovatriptan and/or R-3-ethylamino-6-carboxamido-l,2,3,4-tetrahydrocarbazole is used as internal or external reference marker, or as internal or external reference standard.
  • the method of the second aspect of the present invention is for analysing frovatriptan monosuccinate. More preferably the method of the second aspect of the present invention is for analysing frovatriptan monosuccinate monohydrate.
  • the chromatographic method is used for the analysis of frovatriptan or a salt thereof that is suitable for use in a pharmaceutical composition.
  • the chromatographic method is used for die analysis of frovatriptan or a salt thereof that has not entered the human or animal body.
  • the frovatriptan or the salt thereof that is analysed is not in contact with a human or animal bodily fluid such as whole blood or plasma.
  • the frovatriptan or the salt thereof that is analysed is not in solution.
  • the chromatographic method is used for the analysis of a pharmaceutical composition comprising frovatriptan or a salt thereof.
  • the chromatographic method is used for the analysis of a substance comprising at least 5% frovatriptan or a salt thereof by weight.
  • the substance comprises at least 10%, at least 25%, at least 50%, at least 75% or at least 90% frovatriptan or a salt thereof by weight.
  • the substance comprises at least 95% frovatriptan or a salt thereof by weight.
  • the chromatographic method is used for the analysis of a substance comprising frovatriptan or a salt thereof as the only active pharmaceutical ingredient.
  • a third aspect of the present invention provides a chromatographic method for analysing frovatriptan or a salt thereof, wherein the mobile phase comprises a formate salt.
  • the counter cation to the formate salt is preferably an ammonium cation, i.e. the formate salt is preferably ammonium formate.
  • die mobile phase comprises an aqueous solution of the formate salt.
  • the formate salt is typically present at a concentration of 0.001 to 0.2 M, preferably at a concentration of 0.005 to 0.1 M, more preferably at a concentration of 0.01 to 0.1 M, and most preferably at a concentration of about 0.02 M.
  • the aqueous solution further comprises a base, more preferably an organic base.
  • the organic base is an amine such as an aU ⁇ lamine.
  • the all ⁇ 1 ⁇ 2mine may be selected from a monoaUcylamine such as ethylamine, n-propylamine or isopropylamine, a diaUtylamine such as diethylamine, N- ethyl-N-methylamine or N-ethyl-N-n-propylamine, a cycHc-aUcylamine such as piperidine, pyrrolidine or morpholine, or a trialfylamine such as triethylamine, dHsopropylethylamine or dimethylethylamine.
  • the alfylamine is a monoaUiylamine such as eti ylamine, n-propylamine or isopropylamine.
  • the base in the aqueous solution can be present at a concentration of 0.001 to 0.2 % v/v, preferably at a concentration of 0.005 to 0.2 % v/v, more preferably at a concentration of 0.01 to 0.2 % v/v, and most preferably at a concentration of about 0.05 % v/v.
  • the pH of the aqueous solution is approximately 7.5 to 10. More preferably the pH of the aqueous solution is approximately 8.5 to 9.5. Most preferably the pH of the aqueous solution is approximately 9.2.
  • 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 formate salt.
  • the first liquid A is an aqueous solution of the formate salt. More preferably die first liquid A is an aqueous solution of a mixture of the formate salt and a base. Most preferably the first liquid A is an aqueous solution of a mixture of the formate salt such as ammonium formate, and an aUiylamine such as n-propylamine.
  • the second liquid B preferably comprises or is an organic solvent, preferably selected from an alcohol, preferably an alkyl alcohol, such as methanol, ethanol, propanol or iso- propanol, or acetonitrile, or a mixture thereof.
  • an alcohol preferably an alkyl alcohol, such as methanol, ethanol, propanol or iso- propanol, or acetonitrile, or a mixture thereof.
  • the second liquid B comprises or is a polar protic organic solvent such as acetic acid, methanol, ethanol, n- propanol, n-butanol, iso-propanol, iso-butanol, sec-butanol or tert-butanol, or a mixture thereof.
  • polar protic organic solvent is an alcohol such as a C C 6 alcohol. More preferably the alcohol is an alkyl alcohol.
  • the alcohol is a C r C 4 alkyl alcohol such as methanol, ethanol, n-propanol, n-butanol, iso-propanol, iso-butanol, sec-butanol or tert-butanol.
  • the second liquid B is methanol.
  • the second liquid B is substantially water miscible.
  • the mobile phase contains less than 10%, less than 5% or less than 1% acetonitrile by volume. In one embodiment, the mobile phase contains no acetonitrile.
  • the mobile phase contains less than 10%, less than 5% or less than 1% of any organic dipolar aprotic solvent by volume. In one embodiment, the mobile phase contains no organic dipolar aprotic solvent.
  • a preferred embodiment of the third aspect of the present invention is when the first liquid A is an aqueous solution of a buffer comprising the formate salt mixed with n- propylamine, and the second liquid B is methanol.
  • a particularly preferred embodiment of the third aspect of the present invention is when the first liquid A is 0.02 M ammonium formate containing 0.1 % v/v n-propylamine and the second liquid B is methanol.
  • 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 still the relative concentration of the liquids A and B by volume is about 50 % A : 50 % B. Alternately, 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 30 to 120 minutes, more preferably 100 % A : 0 % B to 0 % A : 100 % B over a period of 30 to 70 minutes.
  • the chromatographic method of the third aspect of the present invention may comprise a gradient programming so that the relative concentration of the liquids A and B by volume starts at a first ratio, then is varied to a first gradient over a first period of time, to arrive at a second ratio.
  • the first ratio may be 65-85 % A : 15-35 % B.
  • the first ratio is 70-80 % A 30 % B.
  • the first ratio is about 75 % A : 25 % B.
  • the first period of time may be from 0 to 120 minutes.
  • the first period of time is from 30 to 90 minutes.
  • Most preferably the first period of time is about 50 minutes.
  • the second ratio may be 10-30 % A : 70-90 % B.
  • the second ratio is 15-25 % A : 75-85 % B.
  • the second ratio is about 20 % A : 80 % B.
  • a particularly preferred method according to the third aspect of the present invention is when the first liquid A is 0.02 M ammonium formate containing 0.1 % v/v n-propylamine and the second liquid B is methanol and the gradient is as follows:
  • the method of the third aspect of the present 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 still a mobile phase flow rate of between 0.5 and 1.5 ml/min is used, most 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 is chiral and/or the mobile phase further comprises a chiral selector. In other embodiments however the stationary phase used is non-chiral.
  • the stationary phase used in the third aspect of the present 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 Waters XTerra RP18 (250 mm x 4.6 mm), 5 ⁇ column.
  • the stationary phase has a particle size of between 0.1 and ⁇ , or between 0.5 and 25 ⁇ , or between 1 and ⁇ , or between 4.5 and 6 ⁇ . 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 200A. More preferably the stationary phase has a pore size of between 100 and 175A, or between 125 and 15 ⁇ . Most preferably the stationary phase has a pore size of about 137A.
  • the chromatography is carried out in a column between lOmm and 5000mm in length, or in a column between 50mm and 1000mm in length, or between 100mm and 500mm in length. More preferably the chromatography is carried out in a column between 200mm and 280mm in length. Most preferably the chromatography is carried out in a column about 250mm 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.
  • (+)-3-N-benzyl-6-carboxamido-3-N-memylamino-l,2,3,4-tetrahydrocarbazole detects and optionally quantifies in a single run both (+)-3-amino-6-carboxamido-l,2,3,4-tetrahydrocarbazole and (+)-3-N-benzyl-6- carboxamido-3-N-memylamino-l,2,3,4-tetrahydrocarbazole.
  • the chromatographic method according to the third aspect of the present invention efficiently detects and quantifies in a single run all impurities including those selected from the following compounds:
  • (+)-3-amino-6- carboxamido-l,2,3,4-tetrahydrocarbazole and/ or (+)-3-N-benzyl-6-carboxamido-3-N- memylamino-l,2,3,4-tetrahydrocarbazole is used as internal or external reference marker, or as internal or external reference standard.
  • frovatriptan and/or R- 3-emylammo-6-carboxamido-l,2,3,4-tetrahydrocarbazole is used as internal or external reference marker, or as internal or external reference standard.
  • the method of the third aspect of the present invention is for analysing frovatriptan monosuccinate. More preferably the method of the third aspect of the present invention is for analysing frovatriptan monosuccinate monohydrate.
  • the chromatographic method is used for the analysis of frovatriptan or a salt thereof that is suitable for use in a pharmaceutical composition.
  • the chromatographic method is used for the analysis of frovatriptan or a salt thereof that has not entered the human or animal body.
  • the frovatriptan or the salt thereof that is analysed is not in contact with a human or animal bodily fluid such as whole blood or plasma.
  • the frovatriptan or the salt thereof that is analysed is not in solution.
  • the chromatographic method is used for the analysis of a pharmaceutical composition comprising frovatriptan or a salt thereof.
  • the chromatographic method is used for the analysis of a substance comprising at least 5% frovatriptan or a salt thereof by weight.
  • the substance comprises at least 10%, at least 25%, at least 50%, at least 75% or at least 90% frovatriptan or a salt thereof by weight.
  • die substance comprises at least 95% frovatriptan or a salt thereof by weight.
  • the chromatographic method is used for the analysis of a substance comprising frovatriptan or a salt thereof as die only active pharmaceutical ingredient.
  • a fourth aspect of the present invention provides a chromatographic method for analysing frovatriptan or a salt thereof, wherein the stationary phase is reverse phase and the mobile phase comprises an al lamine.
  • the alkylamine may be selected from a monoalkylamine such as emylamine, n-propylamine or isopropylamine, a dialkylamine such as diediylamine, N-emyl-N-methylamine or N- emyl-N-n-propylamine, a cyclic-alkylamine such as piperidine, pyrrolidine or morpholine, or a triaUiylamine such as triethylamine, diisopropylethylamine or dimemylethylamine.
  • the alkylamine is a monoalkylamine such as ethylamine, n-propylamine or isopropylamine. More preferably the aUcylamine is n-propylamine.
  • the mobile phase comprises an aqueous solution of the aUcylamine.
  • the allcylamine is typically present at a concentration of 0.001 to 0.2 % v/v, preferably at a concentration of 0.005 to 0.2 % v/v, more preferably at a concentration of 0.01 to 0.2 % v/v, and most preferably at a concentration of about 0.05 % v/v.
  • the aqueous solution further comprises a carboxylate salt.
  • the carboxylate salt is an acetate salt, a formate salt or a trifluoroacetate salt. More preferably the carboxykte salt is a formate salt such as ammonium formate.
  • the aqueous solution comprises a carboxykte salt, preferably the counter cation to the carboxykte salt is an ammonium cation.
  • the carboxykte salt is typically present in the aqueous solution at a concentration of 0.001 to 0.2 M, preferably at a concentration of 0.005 to 0.1 M, more preferably at a concentration of 0.01 to 0.1 M, and most preferably at a concentration of about 0.02 M.
  • the pH of the aqueous solution is approximately 7.5 to 10. More preferably the pH of the aqueous solution is approximately 8.5 to 9.5. Most preferably the pH of the aqueous solution is approximately 9.2.
  • die 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 alkylamine.
  • the first liquid A is an aqueous solution of the aUiylamine. More preferably the first liquid A is an aqueous solution of a mixture of the alkylamine and a carboxykte salt.
  • the first liquid A is an aqueous solution of a mixture of a formate salt such as ammonium formate, and an allcylamine such as n-propykmine.
  • the second liquid B preferably comprises or is an organic solvent, preferably selected from an alcohol, preferably an alkyl alcohol, such as methanol, ethanol, propanol or iso- propanol, or acetonitrile, or a mixture thereof.
  • the second liquid B comprises or is a polar protic organic solvent such as acetic acid, methanol, ethanol, n- propanol, n-butanol, iso-propanol, iso-butanol, sec-butanol or tert-butanol, or a mixture thereof.
  • the polar protic organic solvent is an alcohol such as a C r C 6 alcohol.
  • the alcohol is an alkyl alcohol. More preferably still the alcohol is a C r C 4 alkyl alcohol such as methanol, ethanol, n-propanol, n-butanol, iso-propanol, iso-butanol, sec-butanol or tert-butanol. Most preferably the second liquid B is methanol. In another embodiment of the fourth aspect of the present invention, the second liquid B is substantially water miscible.
  • the mobile phase contains less than 10%, less than 5% or less than 1% acetonitrile by volume. In one embodiment, the mobile phase contains no acetonitrile.
  • the mobile phase contains less than 10%, less than 5% or less than 1% of any organic dipolar aprotic solvent by volume. In one embodiment, the mobile phase contains no organic dipolar aprotic solvent.
  • a preferred embodiment of the fourth aspect of the present invention is when the first liquid A is an aqueous solution of a buffer comprising a formate salt mixed with n- propylamine, and the second liquid B is methanol.
  • a particularly preferred embodiment of the fourth aspect of the present invention is when the first liquid A is 0.02 M ammonium formate containing 0.1 % v/v n-propylamine and the second liquid B is methanol.
  • 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 still the relative concentration of the liquids A and B by volume is about 50 % A : 50 % 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 30 to 120 minutes, more preferably 100 % A : 0 % B to 0 % A : 100 % B over a period of 30 to 70 minutes.
  • the chromatographic method of the fourth aspect of the present invention may comprise a gradient programming so that the relative concentration of the liquids A and B by volume starts at a first ratio, then is varied to a first gradient over a first period of time, to arrive at a second ratio.
  • the first ratio may be 65-85 % A : 15-35 % B.
  • the first ratio is 70-80 % A : 20- 30 % B.
  • Most preferably the first ratio is about 75 % A : 25 % B.
  • the first period of time may be from 0 to 120 niinutes. Preferably the first period of time is from 30 to 90 minutes. Most preferably the first period of time is about 50 minutes.
  • the second ratio may be 10-30 % A : 70-90 % B. Preferably the second ratio is 15-25 % A : 75-85 % B. Most preferably the second ratio is about 20 % A : 80 % B.
  • a particularly preferred method according to the fourth aspect of the present invention is when the first liquid A is 0.02 M ammonium formate containing 0.1 % v/v n-propylamine and the second liquid B is methanol and the gradient is as follows:
  • the method of the fourth aspect of the present 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 still a mobile phase flow rate of between 0.5 and 1.5 ml/min is used, most preferably a mobile phase flow rate of about 1 ml/ min is used.
  • the reverse phase stationary phase used is a gel, preferably a silica gel.
  • the stationary phase used is chiral and/or the mobile phase further comprises a chiral selector. In odier embodiments however the stationary phase used is non-chiral.
  • the reverse phase stationary phase used in the fourth aspect of the present invention is selected from an octadecylsilyl silica gel, an octylsilyl silica gel, a phenylalkyl silica gel, a cyanopropyl silica gel, an 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 Waters XTerra RP18 (250 mm x 4.6 mm), 5 ⁇ column.
  • the stationary phase has a particle size of between 0.1 and ⁇ , or between 0.5 and 25 ⁇ , or between 1 and ⁇ , or between 4.5 and 6 ⁇ . 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 between 100 and 175A, or between 125 and 15 ⁇ . Most preferably the stationary phase has a pore size of about 137A.
  • the chromatography is carried out in a column between 10mm and 5000mm in length, or in a column between 50mm and 1000mm in length, or between 100mm and 500mm in length. More preferably the chromatography is carried out in a column between 200mm and 280mm in length. Most preferably the chromatography is carried out in a column about 250mm 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.
  • the chromatographic method detects and optionally quantifies in a single run one or more impurities selected from:
  • the chromatographic method detects and optionally quantifies in a single run both (+)-3-amino-6-carboxaniido-l,2,3,4-tetrahydiOcarbazole and (+)-3-N-benzyl-6- carboxamido-3-N-memylamino- 1 ,2,3,4-tetrahydrocarbazole.
  • the chromatographic method according to the fourth aspect of the present invention efficiently detects and quantifies in a single run all impurities including those selected from the following compounds:
  • (+)-3-amino-6- carboxamido-l,2,3,4-tetrahydrocarbazole and/ or (+)-3-N-benzyl-6-carboxamido-3-N- memylamino-l,2,3,4-tetrahydrocarbazole is used as internal or external reference marker, or as internal or external reference standard.
  • frovatriptan and/ or R-3-emylamino-6-carboxamido-l,2,3,4-tetrahydrocarbazole is used as internal or external reference marker, or as internal or external reference standard.
  • the method of the fourth aspect of the present invention is for analysing frovatriptan monosuccinate. More preferably the method of the fourth aspect of the present invention is for analysing frovatriptan monosuccinate monohydrate.
  • the chromatographic method is used for the analysis of frovatriptan or a salt thereof that is suitable for use in a pharmaceutical composition.
  • the chromatographic method is used for the analysis of frovatriptan or a salt thereof that has not entered the human or animal body.
  • the frovatriptan or the salt thereof that is analysed is not in contact with a human or animal bodily fluid such as whole blood or plasma.
  • the frovatriptan or the salt thereof that is analysed is not in solution.
  • the chromatographic method is used for the analysis of a pharmaceutical composition comprising frovatriptan or a salt thereof.
  • the chromatographic method is used for the analysis of a substance comprising at least 5% frovatriptan or a salt thereof by weight.
  • the substance comprises at least 10%, at least 25%, at least 50%, at least 75% or at least 90% frovatriptan or a salt thereof by weight.
  • the substance comprises at least 95% frovatriptan or a salt thereof by weight.
  • the chromatographic method is used for the analysis of a substance comprising frovatriptan or a salt thereof as the only active pharmaceutical ingredient.
  • a fifth aspect of the present invention provides a method for analysing a substance, comprising the detection and optional quantification of (+)-3-amino-6-carboxamido- 1,2,3,4-tetrahydrocarbazole and/ or (+)-3-N-benzyl-6-carboxamido-3-N-memylamino- 1,2,3,4-tetrahydrocarbazole, wherein the substance comprises an active pharmaceutical ingredient.
  • the method of the fifth aspect of the present invention comprises the detection and optional quantification of both (+)-3-aniino-6-carboxarnido-l, 2,3,4- tetrahydrocarbazole and (+)-3-N-benzyl-6-carboxamido-3-N-memylamino-l ,2,3,4- tetrahydrocarbazole.
  • the method further comprises the detection and optional quantification of frovatriptan or a salt thereof.
  • the substance is an active pharmaceutical ingredient.
  • the substance comprises or is frovatriptan, optionally in the form of a salt, solvate, hydrate or anhydrate. More preferably the frovatriptan is in the form of frovatriptan monosuccinate. Most preferably the frovatriptan is in the form of frovatriptan monosuccinate monohydrate.
  • the substance is for use in a pharmaceutical composition.
  • 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 whole blood or plasma.
  • the substance that is analysed is not in solution.
  • the method is a method of analysing a pharmaceutical composition comprising frovatriptan or a salt thereof.
  • the substance comprises at least 5% frovatriptan or a salt thereof by weight.
  • the substance comprises at least 10%, at least 25%, at least 50%, at least 75% or at least 90% frovatriptan or a salt thereof by weight.
  • the substance comprises at least 95% frovatriptan or a salt thereof by weight.
  • the substance comprises frovatriptan or a salt thereof as the only active pharmaceutical ingredient.
  • the method is a chromatographic method, preferably wherein the mobile phase 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 selected from an acid, an organic salt, an inorganic salt, an organic base (such as a diaUcylamine or a or a mixture thereof.
  • the buffer is a phosphate salt, an acetate salt, a formate salt, a trifluoroacetate salt, a phosphoric acid, acetic acid, formic acid, trifluoroacetic acid, an aU ⁇ ylamine such as diemylamine, n-propykmine or triemylarnine, or a mixture thereof. More typically, the buffer is a phosphate salt, an acetate salt, a formate salt, acetic acid, trifluoroacetic acid, c ethylamine, n-propylamine, triethylamine or a mixture thereof. In one embodiment of the fifth aspect of the present invention, the buffer comprises a carboxylate salt and/ or an organic base.
  • the carboxylate salt is an acetate salt, a formate salt or a trifluoroacetate salt. More preferably the carboxylate salt is a formate salt such as ammonium formate.
  • the organic base is an amine such as an alfylamine.
  • the alfylamine may be selected from a monoalliylamine such as ethylamine, n-propylarnine or isopropylamine, a dialliylamine such as cUethylamine, N-e yl-N-memylamine or N- ethyl-N-n-propylamine, a cyclic-alkykinine such as piperidine, pyrrolidine or morpholine, or a ttialkylamine such as triethylamine, dHsopropylethylamine or dimemylemylamine.
  • a monoalliylamine such as ethylamine, n-propylarnine or isopropylamine
  • a dialliylamine such as cUethylamine, N-e yl-N-memylamine or N- ethyl-N-n-propylamine
  • the aUtylarnine is a monoaUcylainine such as emylamine, n-propylamine or isopropylamine. More preferably the aUcylamine is n-propylamine.
  • the buffer is or comprises a salt
  • the counter cation is an ammonium cation.
  • the buffer is a mixture of a formate salt, such as ammonium formate, and a base, more preferably an organic base, such as n-propylamine.
  • the salt in the buffer can be present at a concentration of 0.001 to 0.2 M, preferably at a concentration of 0.005 to 0.1 M, more preferably at a concentration of 0.01 to 0.1 M, and most preferably at a concentration of about 0.02 M; and/ or d e base in the buffer can be present at a concentration of 0.001 to 0.2 % v/v, preferably at a concentration of 0.005 to 0.2 % v/v, more preferably at a concentration of 0.01 to 0.2 % v/v, and most preferably at a concentration of about 0.05 % v/v.
  • the buffer is a mixture of ammonium formate present at a concentration of 0.01 to 0.1 M and n-propylamine at a concentration of 0.01 % to 0.2 % v/v.
  • the buffer is a mixture of ammonium formate present at a concentration of about 0.02 M and n-propylamine at a concentration of about 0.1 % v/v.
  • the pH of the buffer solution is approximately 7.5 to 10. More preferably the pH of the buffer solution is approximately 8.5 to 9.5. Most preferably the pH of the buffer solution is approximately 9.2.
  • the second liquid B preferably comprises or is an organic solvent, preferably selected from an alcohol, preferably an alkyl alcohol, such as methanol, ethanol, propanol or iso- propanol, or acetonitrile, or a mixture thereof.
  • the second liquid B comprises or is a polar protic organic solvent such as acetic acid, methanol, ethanol, n- propanol, n-butanol, iso-propanol, iso-butanol, sec-butanol or tert-butanol, or a mixture thereof.
  • polar protic organic solvent is an alcohol such as a Q-Q alcohol. More preferably the alcohol is an alkyl alcohol.
  • the alcohol is a C r C 4 alkyl alcohol such as methanol, ethanol, n-propanol, n-butanol, iso-propanol, iso-butanol, sec-butanol or tert-butanol.
  • die second liquid B is methanol.
  • the second liquid B is substantially water miscible.
  • the mobile phase contains less than 10%, less than 5% or less than 1% acetonitrile by volume. In one embodiment, the mobile phase contains no acetonitrile.
  • the mobile phase contains less than 10%, less than 5% or less than 1% of any organic dipolar aprotic solvent by volume. In one embodiment, the mobile phase contains no organic dipolar aprotic solvent.
  • a preferred embodiment of the fifth aspect of the present invention is when the first liquid A is an aqueous solution of a buffer comprising a formate salt mixed with n-propylamine, and the second liquid B is methanol.
  • a particularly preferred embodiment of the fifth aspect of the present invention is when the first liquid A is 0.02 M ammonium formate containing 0.1 % v/v n-propylamine and the second liquid B is methanol.
  • 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.
  • said method detects and optionally quantifies in a single run (+)-3-amino-6-carboxaudido- 1 ,2,3,4-tetrahydrocarbazole and/or (+)-3-N-benzyl-6-carboxamido-3-N-memylamino- 1,2,3,4-tetrahydrocarbazole. More preferably said method also detects and optionally quantifies in the same run frovatriptan or a salt thereof.
  • said method detects and optionally quantifies in a single run all three of: frovatriptan or a salt thereof;
  • (+)-3-N-benzyl-6-carboxarmdo-3-N-memylamino-l,2,3,4-tetrahydrocarbazole In one embodiment of the fifth aspect of the present invention, (+)-3-amino-6- carboxamido-l,2,3,4-tetrahydrocarbazole and/ or (+)-3-N-benzyl-6-carboxamido-3-N- memylamino-l,2,3,4-tetrahydrocarbazole is used as internal or external reference marker, or as internal or external reference standard.
  • frovatriptan and/or R- 3-emylaiTiino-6-carboxamido-l,2,3,4-tetrahydrocarbazole is used as internal or external reference marker, or as internal or external reference standard.
  • 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 still the relative concentration of the liquids A and B by volume is about 50 % A : 50 % 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 30 to 120 minutes, more preferably 100 % A : 0 % B to 0 % A : 100 % B over a period of 30 to 70 minutes.
  • the chromatographic method of the fifth aspect of the present invention may comprise a gradient programming so that the relative concentration of the liquids A and B by volume starts at a first ratio, then is varied to a first gradient over a first period of time, to arrive at a second ratio.
  • the first ratio may be 65-85 % A : 15-35 % B. Preferably the first ratio is 70-80 % A : 20- 30 % B. Most preferably the first ratio is about 75 % A : 25 % B.
  • the first period of time may be from 0 to 120 minutes. Preferably the first period of from 30 to 90 minutes. Most preferably the first period of time is about 50 minutes.
  • the second ratio may be 10-30 % A : 70-90 % B. Preferably the second ratio is 15-25 % A : 75-85 % B. Most preferably the second ratio is about 20 % A : 80 % B.
  • a particularly preferred method according to the fifth aspect of the present invention is when the first liquid A is 0.02 M ammonium formate containing 0.1 % v/v n-propylamine and the second liquid B is methanol and the gradient is as follows:
  • the method of the fifth aspect of the present 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 still a mobile phase flow rate of between 0.5 and 1.5 ml/min is used, most 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 is chiral and/or the mobile phase further comprises a chiral selector. In other embodiments however the stationary phase used is non-chiral.
  • the stationary phase used in the fifth aspect of the present 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 Waters XTerra RP18 (250 mm x 4.6 mm), 5 ⁇ column.
  • the stationary phase has a particle size of between 0.1 and ⁇ , or between 0.5 and 25 ⁇ , or between 1 and ⁇ , or between 4.5 and 6 ⁇ . 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 between 100 and 75A, or between 125 and 15 ⁇ . Most preferably die stationary phase has a pore size ot about 137A.
  • the chromatography is carried out in a column between 10mm and 5000mm in length, or in a column between 50mm and 1000mm in length, or between 100mm and 500mm in length. More preferably the chromatography is carried out in a column between 200mm and 280mm in length. Most preferably the chromatography is carried out in a column about 250mm in length.
  • the chromatography may be carried out in a column between 0.01mm and 100mm in internal diameter, or between O.lmm 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.
  • a sixth aspect of the present invention provides a process for preparing a batch of a substance, said process comprising the steps of:
  • the substance comprises or is an active pharmaceutical ingredient.
  • the substance comprises or is frovatriptan, optionally in the form of a salt, solvate, hydrate or anhydrate. More preferably the frovatriptan is in the form of frovatriptan monosuccinate. Most preferably the frovatriptan is in the form of frovatriptan monosuccinate monohydrate.
  • the substance is for use in a pharmaceutical composition.
  • the substance comprises or is a pharmaceutical composition.
  • the pharmaceutical composition comprises frovatriptan, optionally in the form of a salt, solvate, hydrate or anhydrate. More preferably the frovatriptan is in the form of frovatriptan monosuccinate. Most preferably the frovatriptan is in the form of frovatriptan monosuccinate monohydrate.
  • the pharmaceutical composition comprises one or more pharmaceutically acceptable excipients.
  • the substance of the sixth aspect of the present invention has not entered the human or animal body.
  • the substance is not in contact with a human or animal bodily fluid such as whole blood or plasma.
  • the substance is not in solution.
  • the substance comprises at least 5% frovatriptan or a salt thereof by weight.
  • the substance comprises at least 10%, at least 25%, at least 50%, at least 75% or at least 90% frovatriptan or a salt thereof by weight.
  • the substance comprises at least 95% frovatriptan or a salt thereof by weight.
  • the substance comprises frovatriptan or a salt thereof as the only active pharmaceutical ingredient.
  • a seventh aspect of the present invention provides a batch of frovatriptan or a salt thereof which has been prepared by a process according to the sixth aspect of the present invention.
  • the frovatriptan is substantially free of (+)-3-arrrmo-6-carboxamido- 1, 2,3,4- tetrahydrocarbazole and/ or (+)-3-N-benzyl-6-carboxamido-3-N-methylamino- 1 ,2,3,4-tetrahydrocarbazole.
  • Frovatriptan or a salt thereof 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 present invention provides a process for preparing a pharmaceutical composition, said process comprising the step of combining one or more pharmaceutically acceptable excipients with part or all of a batch of frovatriptan or a salt thereof which has been prepared by a process according to the sixth aspect of the present invention.
  • a ninth aspect of the present invention provides a pharmaceutical composition prepared by a process according to the eighth aspect of the present invention.
  • a tenth aspect of the present invention provides a batch of one or more pharmaceutical compositions which have been prepared by a process according to the sixth aspect of the present invention, wherein the pharmaceutical composition(s) comprise frovatriptan or a salt thereof.
  • the pharmaceutical composition(s) also comprise one or more pharmaceutically acceptable excipients.
  • any embodiment of a given aspect of the present invention may occur in combination with any other embodiment of the same aspect of the present invention.
  • any preferred or optional embodiment of any aspect of the present invention should also be considered as a preferred or optional embodiment of any other aspect of the present invention.
  • the present invention can be used to analyse frovatriptan and/or its salts, in particular frovatriptan monosuccinate monohydrate, as an API or when prepared as a pharmaceutical composition.
  • the pharmaceutical compositions that can be analysed by the present 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, inhalation 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 particularly convenient for analysing frovatriptan, particularly with respect to the related substances formed in the synthesis of frovatriptan and/ or its salts prepared by the process disclosed in co-pending Indian patent application IN 657/KOL/2009 and the corresponding international patent application WO 2010/122343.
  • the present invention solves this problem and efficiently detects and quantifies, in a single run, all impurities and intermediates formed in this particular synthetic process.
  • the present invention is advantageous as the gradient method allows the elution of all polar to non-polar impurities. Identification of all impurities in a single run is particularly advantageous and cost saving in a commercial environment.
  • the present invention is also advantageous as the method is selective, linear and precise for the analysis of related substances in frovatriptan and/ or its salts.
  • the present invention is highly sensitive and allows detection and quantification of related substances in frovatriptan and/ or its salts at levels much lower than acceptance limits specified by health authorities.
  • the method of the present invention can be used to easily detect and quantify all degradation impurities formed on storage of samples of frovatriptan. 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 (Reproducibility), 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 and mixtures thereof.
  • the buffer can be an organic salt such as the ammonium salt of acetate or formate and mixtures thereof.
  • the buffer can be a mineral acid or a carboxylic acid, such as acetic acid or trifiuoroacetic acid.
  • the buffer can be an organic base such as a mono-, di- or ttiaUcylamine, such as diemylamine, n-propylamine or trie ylamine.
  • the first liquid A is a mixture of 0.02 M ammonium formate and 0.1 % v/v n-propylamine.
  • the second liquid B is an organic solvent such as an alcohol, preferably a C, to C 6 alkyl alcohol like methanol, ethanol, propanol, butanol or iso-propanol or mixtures thereof.
  • the organic solvent(s) may be tetrahydrofuran, ethyl acetate or acetonitrile or any suitable organic solvent(s).
  • the organic solvent is methanol.
  • the stationary phase used in the method of the present 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 present invention if required.
  • concentration of the components analysed may be determined by comparison with one or more external reference compounds.
  • the inventors have tested the methods of the present invention extensively to show that they are reproducible, precise and linear with respect to concentration.
  • Injection volume 20 ⁇ ;
  • the sample of frovatiiptan monosuccinate monohydrate is initially dissolved in a small volume of the diluent; the sample solution is then injected into die column which is run using the mobile phase outlined below;
  • First Liquid A a mixture of 0.02 M ammonium formate and 0.1 % v/v n-propylamine; Second Liquid B: methanol;

Abstract

La présente invention concerne une nouvelle méthode HPLC pour l'analyse de la substance médicamenteuse frovatriptan et de substances apparentées. La présente invention concerne notamment une nouvelle méthode HPLC pour l'analyse de la substance médicamenteuse monohydrate de monosuccinate de frovatriptan et de substances apparentées. Dans un premier procédé, la phase mobile comprend deux liquides ou plus et la concentration relative des liquides est variée selon un gradient prédéterminé. Dans d'autres procédés, la phase stationnaire est une phase inverse et la phase mobile comprend un alcool et/ou une alkylamine. Dans un autre procédé, la phase mobile comprend un sel de formate. Un procédé final comprend la détection et éventuellement la quantification d'impuretés spécifiques. La présente invention concerne également le frovatriptan et des compositions pharmaceutiques associées à partir desquelles des échantillons ont été analysés selon les procédés de l'invention et/ou qui sont essentiellement exemptes d'impuretés spécifiques.
PCT/GB2011/050168 2010-02-02 2011-02-01 Méthode hplc pour l'analyse de frovatriptan WO2011095803A1 (fr)

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IN99/KOL/2010 2010-02-02

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
CN112326832A (zh) * 2020-11-04 2021-02-05 北京林业大学 一种沙棘中5-羟色胺和白藜芦醇的检测方法

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994014772A1 (fr) * 1992-12-21 1994-07-07 Smithkline Beecham Plc Enantiomeres de derives du carbazole utilises comme agonistes similaires a la 5-ht1
WO1999054302A1 (fr) * 1998-04-16 1999-10-28 Vernalis Limited Procede de production de r-(+)-6-carboxamido-3-n-methylamino-1,2,3,4-tetrahydrocarbazole
WO2008128225A1 (fr) * 2007-04-16 2008-10-23 Momenta Pharmaceuticals, Inc. Procédés de chromatographie multidimensionnelle permettant de séparer des n-glycanes
WO2009056872A2 (fr) * 2007-10-29 2009-05-07 Generics [Uk] Limited Nouveaux procédés de chromatographie
WO2009077784A2 (fr) * 2007-12-14 2009-06-25 Generics [Uk] Limited Nouveau procédé de clhp
WO2010122343A1 (fr) 2009-04-23 2010-10-28 Generics [Uk] Limited Procédé pour la préparation de frovatriptan et de succinate de frovatriptan et de leurs produits intermédiaires de synthèse

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994014772A1 (fr) * 1992-12-21 1994-07-07 Smithkline Beecham Plc Enantiomeres de derives du carbazole utilises comme agonistes similaires a la 5-ht1
WO1999054302A1 (fr) * 1998-04-16 1999-10-28 Vernalis Limited Procede de production de r-(+)-6-carboxamido-3-n-methylamino-1,2,3,4-tetrahydrocarbazole
WO2008128225A1 (fr) * 2007-04-16 2008-10-23 Momenta Pharmaceuticals, Inc. Procédés de chromatographie multidimensionnelle permettant de séparer des n-glycanes
WO2009056872A2 (fr) * 2007-10-29 2009-05-07 Generics [Uk] Limited Nouveaux procédés de chromatographie
WO2009077784A2 (fr) * 2007-12-14 2009-06-25 Generics [Uk] Limited Nouveau procédé de clhp
WO2010122343A1 (fr) 2009-04-23 2010-10-28 Generics [Uk] Limited Procédé pour la préparation de frovatriptan et de succinate de frovatriptan et de leurs produits intermédiaires de synthèse

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
G. LUNN: "HPLC Methods for Recently Approved Pharmaceuticals", 2005, WILLEY INTERSCIENCE, pages: 286 - 287
KHAN ET AL: "Chiral separation of Frovatriptan isomers by HPLC using amylose based chiral stationary phase", JOURNAL OF CHROMATOGRAPHY B: BIOMEDICAL SCIENCES & APPLICATIONS, ELSEVIER, AMSTERDAM, NL, vol. 846, no. 1-2, 26 January 2007 (2007-01-26), pages 119 - 123, XP005862581, ISSN: 1570-0232, DOI: DOI:10.1016/J.JCHROMB.2006.08.033 *
L. LAUGHER ET AL., CHROMATOGRAPHIA, vol. 52, 2000, pages S113 - S119
LAUGHER ET AL: "Development of an analytical methodology from toxicokinetic to clinical studies for the anti-migraine drug Frovatriptan", CHROMATOGRAPHIA SUPPLEMENT, vol. 52, 2000, pages 113 - 119, XP002634445 *
M. KHAN ET AL., J, CHROMATOGRAPHY B, vol. 846, no. 1-2, 2007, pages 119 - 123

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
CN112326832A (zh) * 2020-11-04 2021-02-05 北京林业大学 一种沙棘中5-羟色胺和白藜芦醇的检测方法

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