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WO2015005928A1 - Procédé analytique pour détecter des oligosaccharides sulfatés - Google Patents

Procédé analytique pour détecter des oligosaccharides sulfatés Download PDF

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Publication number
WO2015005928A1
WO2015005928A1 PCT/US2013/050147 US2013050147W WO2015005928A1 WO 2015005928 A1 WO2015005928 A1 WO 2015005928A1 US 2013050147 W US2013050147 W US 2013050147W WO 2015005928 A1 WO2015005928 A1 WO 2015005928A1
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WO
WIPO (PCT)
Prior art keywords
mobile phase
hilic
poly
column
salt
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2013/050147
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English (en)
Inventor
Helen CHAO
ChungYao WANG
Imin HUANG
ChiaYen WU
YungTe CHIANG
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Scinopharm Taiwan Ltd
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Scinopharm Taiwan Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Scinopharm Taiwan Ltd filed Critical Scinopharm Taiwan Ltd
Priority to KR1020167003059A priority Critical patent/KR20160030963A/ko
Priority to CA2917460A priority patent/CA2917460A1/fr
Priority to CN201380078160.1A priority patent/CN105431733B/zh
Priority to JP2016525337A priority patent/JP6208866B2/ja
Priority to AU2013393832A priority patent/AU2013393832B2/en
Priority to EP13888999.3A priority patent/EP3019861A4/fr
Priority to PCT/US2013/050147 priority patent/WO2015005928A1/fr
Publication of WO2015005928A1 publication Critical patent/WO2015005928A1/fr
Priority to IL243405A priority patent/IL243405A0/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D15/00—Separating processes involving the treatment of liquids with solid sorbents; Apparatus therefor
    • B01D15/08—Selective adsorption, e.g. chromatography
    • B01D15/26—Selective adsorption, e.g. chromatography characterised by the separation mechanism
    • B01D15/30—Partition chromatography
    • B01D15/305—Hydrophilic interaction chromatography [HILIC]
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
    • C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
    • C08B37/0075—Heparin; Heparan sulfate; Derivatives thereof, e.g. heparosan; Purification or extraction methods thereof
    • C08B37/0078—Degradation products
    • 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
    • G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
    • G01N2030/8809—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample
    • G01N2030/8813—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample biological materials
    • G01N2030/8836—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample biological materials involving saccharides
    • 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
    • G01N30/62—Detectors specially adapted therefor
    • G01N30/72—Mass spectrometers
    • G01N30/7233—Mass spectrometers interfaced to liquid or supercritical fluid chromatograph

Definitions

  • Heparnoid Heparin and Heparan sulfate
  • LMWH low-molecular weight heparin
  • Fondaparinux sodium CAS 1 14870-03-0
  • CAS 1 14870-03-0 is a member of
  • oligosaccharides / heparins with a chemical name of 0-[2-Deoxy-6-0-sulfo-2-(su!foamino)- alpha-D-glucopyranosyl]-( 1 ⁇ 4)-0-(beta-D-glucopyranurosonyl)-( 1 -4)-0-[2-deoxy-3,6-di-0- sulfb-2-(sulfoaminc -aipha. ⁇ D-g]u ⁇
  • Catalan et al. ( Anal Chem. 2009, 81, 3485) and Tatiana et al, ( Anal Chem. 2006, 78, 1774) have each described the characterization of poly-sulfated oligosaccharides by using electrospray ionization mass spectrometry (ESI-MS) and matrix-assisted laser desorption and ionization mass spectrometry (MALDI-MS).
  • ESI-MS electrospray ionization mass spectrometry
  • MALDI-MS matrix-assisted laser desorption and ionization mass spectrometry
  • oligosaccharides are due to the non-chromophore characteristics (very low UV absorption) of poly-sulfated oligosaccharides, which can restrict the use of traditional UV detectors.
  • the other universal detectors such as refractive index (RI) and evaporative light scattering (ELSD) also lack enough detecting sensitivity for poly-sulfate oligosaccharides.
  • RI refractive index
  • ELSD evaporative light scattering
  • HILIC-UPLC hydrophilic interaction ultra-performance liquid chromatography
  • CAD charged aerosol detector
  • MS mass spectrometer
  • HILIC overcomes the challenge of retaining and separating extremely polar oligosaccharides.
  • the retention mechanism for HILIC is very intricate and is a multi-modal combination of liquid-liquid partitioning, adsorption, ionic interaction and hydrophobic interaction. Therefore, HILIC, in comparison to reverse phase liquid chromatography (RPLC), provides unique selectivity and retention characteristics,
  • the stationary phase used in HILIC column is, in one group of embodiments, an amide-bonded stationary phase.
  • the mobile phase used in HILIC column comprises a salt, in one group of embodiments, the salt is ammonium formate.
  • the concentration of the salt is higher than 50 mM. In some selected embodiments, the concentration is higher than 100 mM.
  • the molar strength of the salt additive in the mobile phase composition can have a significant impact on
  • the solvent of the mobile phase used in the HILIC column is acetonitriie.
  • the detector used for the quantitation of poly-sulfated oligosaccharides is a charged aerosol detector (CAD).
  • CAD charged aerosol detector
  • aerosol particles are charged with an ionized gas (typically nitrogen). After the removal of high-mobility particles (mainly excess N 2 ions), the aerosol particles are then electrically measured. Most importantly, the method has been demonstrated to provide a uniform response for nonvolatile analytes independent of their nature.
  • a separation technique utilizing HILIC, or HILIC-UPLC and (2) a detection technique such as MS or CAD allows for detection, identification and/or quantification of poly-sulfated thereby providing an effective way for analysis of synthetic poly-sulfated oligosaccharides.
  • the poly-sulfated oilgosaccharide detected and/or quantitated by the methods described herein is Fondaparinux sodium.
  • Figure 1(a) provides the chromatograms of HiLIC-CAD for Fondaparinux Sodium using Merck, Sequant Zic®-Hilic (3. Sum 2.1 x250mm).
  • Figure 1(b) provides the chromatograms of HILIC-C AD for Fondaparinux Sodium using Merck, Sequant Zic®-pHiiic (Sum 4.6x 150mm).
  • Figure 1(c) provides the chromatograms of HILIC-CAD for Fondaparinux Sodium using Phenomenex, Synergi Polar-RP (4ura 4.6x250mm).
  • Figure 1(d) provides the chromatograms of HILIC-CAD for Fondaparinux Sodium using Phenomenex, Synergi Fusion-RP (4um 4.6x150mm).
  • Figure 1(e) provide the chromatograms of HI LIC-CAD for Fondaparinux Sodium using Sepax Polar-Pyridine (1.8um 2.1 x 150mm).
  • Figure 1(f) provides the chromatograms of HILIC-CAD for Fondaparinux Sodium using ES, Epic Dio! (1 Jurn 2.1 ⁇ 150mm),
  • Figure 1(g) provides the chromatograms of HILIC-CAD for Fondaparinux Sodium using Waters, Acquity BEH HILIC (1.7urn 2.1 x 150mm).
  • Figure 1(h) provides the chromatograms of HILIC-CAD for Fondaparinux Sodium using Waters, Acquity BEH Amide (1.7um 2, l x 150mm).
  • Figure 2 provides the chromatogram for Fondaparinux Sodium using Waters, BEH .Amide column (a) full scale and (b) expanded scale.
  • Figure 3 provides the chromatograms in expanded scale of the drug substance analyzed using different types of salt (a) 50 niM ammonium formate (b) 100 mM ammonium formate (c) 100 mM pyridinium formate and (d) 50 mM ammonium acetate
  • Figure 4 provides the chromatograms in expanded scale of the drag substance analyzed using various concentrations of ammonium formate (in expanded scale) (a) 50 mM (b) 100 mM (c) 125 mM (d) 1 50 mM (e) 175 mM and (f) 200 mM.
  • Figure 5 provides the chromatograms in expanded scale of the drug substance analyzed using different organic solvents to be mobile phase (a) mobile phase A: 200 mM ammonium formate; mobile phase B: acetone and acetonitrile, 1/1 (b) mobile phase A: 200 mM ammonium formate; mobile phase B: acetonitrile.
  • IPC in-process control
  • H1 L1C column (a) subjecting said sample to chromatography on a hydrophilic interaction ultra-performance liquid chromatography (HILIC-UPLC) column coupled with a charged aerosol detector (CAD) or a mass spectrometer (MS), wherein the stationary phase used in H1 L1C column is an amide- bonded stationary phase; and
  • HILIC-UPLC hydrophilic interaction ultra-performance liquid chromatography
  • CAD charged aerosol detector
  • MS mass spectrometer
  • the samples used in the present methods are typically the output of synthetic production methods of poly-sulfated oligosaccharides.
  • samples of the final step in the synthetic procedures can be analyzed according to the present methods by selecting aliquots of reaction mixtures. The sampling of reaction mixtures allows for detection and/or
  • the sampling of reaction mixture also allows for determination of the extent of completion of a reaction.
  • the final product can be subjected to the present methods to determine if further purification is needed,
  • the conditions for chromatography using hydrophilic interaction ultra-performance liquid chromatography wi ll generally involve those conditions known to one of skill in the art, including, but not limited to column selection (size, length and stationary phase) as well as the mobile phase and/or pH of the mobile phase.
  • the column has a stationary phase of neutral charge (e.g., diol phase or amide phase), a charged stationary phase (e.g., silica phase, aminopropyl phase), or a zwitterionic stationary phase.
  • the stationary phase is an amide-bonded stationary phase. Examples 1 - 10 illustrate the results obtained from the use of various stationary phases using the methods described herein.
  • the solvent used in the mob le phase is generally a polar, aprotic organic solvent or a mixture of polar, aprotic organic solvents.
  • the solvent of the mobile phase used in HTL!C column is acetonitrile, acetone or a mixture of acetonitrile and acetone.
  • Examples 13a- 13d illustrate the effect of various solvents and/or mixtures of solvents in the detection and/or quantitation of poly-sulfated oligosaccharides using the methods described herein.
  • the mobile phase will also comprise a salt, generally a salt selected from ammonium formate, pyridimum formate and ammonium acetate, and mixtures thereof.
  • the mobile phase will comprise ammonium formate.
  • the mobile phase comprises a salt selected from ammonium citrate and/or ammonium oxalate. Examples 1 la-1 Id iiiustrate the effect of various salts in the mobi le phase in the detection and/or quantitation of poly-sulfated oligosaccharides using the methods described herein.
  • the concentration of the salt used in the mobile phase will generally be from 25 to about 400 mM, though some optimal results are found when the salt is present in the mobile phase at concentrations of from 50 to about 200 mM. in some embodiments, the salt is present in the mobile phase at concentrations of about 50-100 mM, from about 100-200 mM, and from about 75 to 175 mM.
  • Examples I2a ⁇ 12d illustrate the effect of various salt concentrations on peak resolution and peak width during the detection and/or quantitation of poly-sulfated oligosaccharides, when using the methods described herein, by employing ammonium formate as the salt,
  • the methods described above are useful for detection and/or quantitation of the poly-sulfated oligosaccharide fondaparinux having the structure:
  • a method for detecting and quantitating fondaparinux in a sample comprising:
  • HILIC-UPLC hydrophilic interaction ultra- performance liquid chromatography
  • CAD charged aerosol detector
  • MS mass spectrometer
  • chromatograms using the methods described herein (e.g., by use of HILIC-UPLC") and peak identification using a coupled techinque such as CAD or MS thereby confirming (detecting) the presence or absence of tbndaparinux and/or impurities in the sample.
  • a coupled techinque such as CAD or MS
  • the instruments involved in UPLC-MS study are Ultimate 3000 (UPLC) and micrOTOF-Q ⁇ TM (MS) which were manufactured by Thermo Fisher Dionex and Bruker Daltonics, respectively.
  • the instruments involved in UPLC-CAD are ACQUITY UPLC® System and Thermo Scientific Dionex Ultra CAD which were manufactured by Waters Corporation and Thermo Fisher Dionex, respectively.
  • the concentration of ammonium formate used in the mobile phase is 100 mM or higher than 100 mM.
  • the volume proportion of ammonium formate : acetonitrile in the mobile phase composition is in the range of 95% - 5% ; 5% - 95%.
  • the concentration of testing sample is from 15 ,ug/rnL to 30 mg/mL.
  • the injection volume of testing sample is from 1 ⁇ to 5 uL.
  • Examples 13a and 13b use the mixtures of acetonitrile and acetone and acetonitrile respectively as the solvent of the mobile phase for analyzing Fondaparinux Sodium according to the present invention.
  • the results shown in Figure 5 indicate no obvious difference in selectivity between acetonitrile system and mixture (acetonitrile and acetone) system, a higher back pressure was observed in the system comprising the acetone/acetonitrile mixture than in the acetonitrile system.

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  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Analytical Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pathology (AREA)
  • Immunology (AREA)
  • General Physics & Mathematics (AREA)
  • Physics & Mathematics (AREA)
  • Materials Engineering (AREA)
  • Organic Chemistry (AREA)
  • Polymers & Plastics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Other Investigation Or Analysis Of Materials By Electrical Means (AREA)
  • Saccharide Compounds (AREA)

Abstract

La présente invention concerne un procédé analytique permettant de détecter et de quantifier des oligosaccharides polysulfatés, notamment le fondaparinux sodique, à l'aide de la chromatographie liquide ultra performance par interaction hydrophile (HILIC-UPLC) couplée à un détecteur d'aérosol chargé (CAD) ou à un spectromètre de masse (MS). Ce procédé analytique permet d'obtenir un contrôle pendant le processus lors d'une synthèse totale d'oligosaccharides hautement sulfatés par séparation, quantification et identification de masse. Des systèmes et des conditions utilisant ces procédés sont également décrits.
PCT/US2013/050147 2013-07-11 2013-07-11 Procédé analytique pour détecter des oligosaccharides sulfatés Ceased WO2015005928A1 (fr)

Priority Applications (8)

Application Number Priority Date Filing Date Title
KR1020167003059A KR20160030963A (ko) 2013-07-11 2013-07-11 황산화 올리고당을 검출하기 위한 분석 방법
CA2917460A CA2917460A1 (fr) 2013-07-11 2013-07-11 Procede analytique pour detecter des oligosaccharides sulfates
CN201380078160.1A CN105431733B (zh) 2013-07-11 2013-07-11 用于检测硫酸化寡糖的分析方法
JP2016525337A JP6208866B2 (ja) 2013-07-11 2013-07-11 硫酸化オリゴ糖を検出する分析法
AU2013393832A AU2013393832B2 (en) 2013-07-11 2013-07-11 Analytical method for detecting sulfated oligosaccharides
EP13888999.3A EP3019861A4 (fr) 2013-07-11 2013-07-11 Procédé analytique pour détecter des oligosaccharides sulfatés
PCT/US2013/050147 WO2015005928A1 (fr) 2013-07-11 2013-07-11 Procédé analytique pour détecter des oligosaccharides sulfatés
IL243405A IL243405A0 (en) 2013-07-11 2015-12-30 Analytical method for the detection of sulfur oligosaccharides

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PCT/US2013/050147 WO2015005928A1 (fr) 2013-07-11 2013-07-11 Procédé analytique pour détecter des oligosaccharides sulfatés

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EP (1) EP3019861A4 (fr)
JP (1) JP6208866B2 (fr)
KR (1) KR20160030963A (fr)
CN (1) CN105431733B (fr)
AU (1) AU2013393832B2 (fr)
CA (1) CA2917460A1 (fr)
IL (1) IL243405A0 (fr)
WO (1) WO2015005928A1 (fr)

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CN105628820A (zh) * 2016-01-08 2016-06-01 东营天东制药有限公司 一种低分子肝素生产过程中游离硫酸根离子快速检测方法
JP2017116421A (ja) * 2015-12-24 2017-06-29 昭和電工株式会社 親水性化合物の分離分析方法
US9902971B2 (en) 2014-06-26 2018-02-27 Regeneron Pharmaceuticals, Inc. Methods for producing a mouse XY embryonic (ES) cell line capable of producing a fertile XY female mouse in an F0 generation
US11166915B2 (en) 2016-09-16 2021-11-09 Leukocare Ag Method for obtaining efficient viral vector-based compositions for vaccination or gene therapy
US11366086B2 (en) * 2017-09-06 2022-06-21 Shanghai Green Valley Pharmaceutical Co., Ltd. Method for determining weight-average molecular weight and content of soluble salt of acidic carbohydrates
US11510871B2 (en) 2016-09-16 2022-11-29 Leukocare Ag Method for producing low viscous and highly concentrated biopharmaceutical drug products in liquid formulation

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JP7045373B2 (ja) * 2017-06-22 2022-03-31 昭和電工株式会社 オリゴヌクレオチドの混合物の分離分析方法
CN109254101B (zh) * 2017-07-13 2021-07-09 中国科学院大连化学物理研究所 一种母乳酸性寡糖净化和分析方法
CN116879411B (zh) * 2018-07-24 2025-11-11 深圳市天道医药有限公司 一种达肝素钠亚硝酸降解产物的分析方法及其应用
WO2020020145A1 (fr) * 2018-07-26 2020-01-30 深圳市海普瑞药业集团股份有限公司 Procédé d'analyse de distribution de chaînes de sucre d'héparine de faible poids moléculaire et son utilisation
CN111239311A (zh) * 2018-11-28 2020-06-05 中国科学院大连化学物理研究所 一种婴幼儿排泄物中酸性糖及酸性糖衍生物的分析方法
CN109633003A (zh) * 2018-12-26 2019-04-16 成都普思生物科技股份有限公司 一种测定远志中远志口山酮ⅲ和3,6，-二芥子酰基蔗糖含量的方法
CN110161147A (zh) * 2019-06-19 2019-08-23 北京三元食品股份有限公司 乳中游离低聚糖的高通量定量测定方法
WO2024257862A1 (fr) * 2023-06-14 2024-12-19 株式会社ダイセル Procédé de séparation d'amine
WO2025075046A1 (fr) * 2023-10-03 2025-04-10 株式会社ダイセル Procédé d'analyse
JP7487987B1 (ja) 2023-12-21 2024-05-21 伊那食品工業株式会社 アガロオリゴ糖の分析方法

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Cited By (7)

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Publication number Priority date Publication date Assignee Title
US9902971B2 (en) 2014-06-26 2018-02-27 Regeneron Pharmaceuticals, Inc. Methods for producing a mouse XY embryonic (ES) cell line capable of producing a fertile XY female mouse in an F0 generation
JP2017116421A (ja) * 2015-12-24 2017-06-29 昭和電工株式会社 親水性化合物の分離分析方法
CN105628820A (zh) * 2016-01-08 2016-06-01 东营天东制药有限公司 一种低分子肝素生产过程中游离硫酸根离子快速检测方法
US11166915B2 (en) 2016-09-16 2021-11-09 Leukocare Ag Method for obtaining efficient viral vector-based compositions for vaccination or gene therapy
US11510871B2 (en) 2016-09-16 2022-11-29 Leukocare Ag Method for producing low viscous and highly concentrated biopharmaceutical drug products in liquid formulation
US12350375B2 (en) 2016-09-16 2025-07-08 Leukocare Ag Method for obtaining efficient viral vector-based compositions for vaccination or gene therapy
US11366086B2 (en) * 2017-09-06 2022-06-21 Shanghai Green Valley Pharmaceutical Co., Ltd. Method for determining weight-average molecular weight and content of soluble salt of acidic carbohydrates

Also Published As

Publication number Publication date
JP6208866B2 (ja) 2017-10-04
KR20160030963A (ko) 2016-03-21
CN105431733A (zh) 2016-03-23
EP3019861A4 (fr) 2017-02-22
AU2013393832A1 (en) 2016-02-04
CA2917460A1 (fr) 2015-01-15
EP3019861A1 (fr) 2016-05-18
IL243405A0 (en) 2016-02-29
AU2013393832B2 (en) 2017-11-30
CN105431733B (zh) 2019-01-22
JP2016524166A (ja) 2016-08-12

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