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WO2017152689A1 - Procédé d'analyse haute sensibilité destiné à la détection d'impuretés génotoxiques d'imatinib - Google Patents

Procédé d'analyse haute sensibilité destiné à la détection d'impuretés génotoxiques d'imatinib Download PDF

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Publication number
WO2017152689A1
WO2017152689A1 PCT/CN2016/111651 CN2016111651W WO2017152689A1 WO 2017152689 A1 WO2017152689 A1 WO 2017152689A1 CN 2016111651 W CN2016111651 W CN 2016111651W WO 2017152689 A1 WO2017152689 A1 WO 2017152689A1
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Prior art keywords
analysis method
imatinib
impurity
solution
liquid chromatography
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Ceased
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PCT/CN2016/111651
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English (en)
Chinese (zh)
Inventor
张翠
刘建
杜祖银
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.)
Jiangsu Hansoh Pharmaceutical Group Co Ltd
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Jiangsu Hansoh Pharmaceutical Group Co Ltd
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Priority to CN201680083444.3A priority Critical patent/CN108780075A/zh
Publication of WO2017152689A1 publication Critical patent/WO2017152689A1/fr
Anticipated expiration legal-status Critical
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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
    • 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
    • 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
    • G01N2030/8872—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 impurities

Definitions

  • the invention relates to a method for analyzing genetic impurities of imatinib, in particular to a method for separating and quantitatively determining the genetic impurities of imatinib by high performance liquid chromatography-mass spectrometry.
  • Imatinib mesylate developed by Novartis, is the world's first marketed tumor-related signaling inhibitor, clinically used to treat the chronic phase of Philadelphia chromosome-positive chronic myeloid leukemia (Ph+CML), In an accelerated or blast phase, an adult patient with a malignant gastrointestinal stromal tumor (GIST) who cannot be removed and/or metastasized is treated.
  • the chemical name of imatinib mesylate is 4-(4-methyl-1-piperazine)methyl-N-4-methyl-3-4-(3-pyridyl)-2-pyrimidinylaminophenyl - benzamide mesylate.
  • Genotoxic impurities are found to be potentially damaging to DNA in in vivo/in vitro assays where DNA reactive substances are the primary study. According to current regulations, genotoxic substances (in vivo) are potentially damaging to DNA at any level of intake, which can lead to tumor production and must be strictly controlled.
  • the compound N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidinamine is an intermediate in the synthesis of imatinib mesylate and is a potential genotoxic impurity.
  • imatinib mesylate bulk drug substance the compound N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine
  • the amine is named as impurity F, and its limit is not more than 20 ppm, and a method for detecting impurity F by high performance liquid chromatography-mass spectrometry is disclosed.
  • the detection limit is calculated by S/N ⁇ 3
  • the limit of quantification is determined by S/N ⁇ 10
  • the impurity F of the method is determined.
  • the detection limit was 0.1 ppm and the limit of quantification was 0.25 ppm.
  • the object of the present invention is to provide an analytical method for high-performance liquid chromatography-mass spectrometry in which imatinib impurity F is better, so that the main component and impurity F can be easily and effectively analyzed, and impurities are simultaneously improved.
  • the sensitivity of the quantitative analysis of F is to provide an analytical method for high-performance liquid chromatography-mass spectrometry in which imatinib impurity F is better, so that the main component and impurity F can be easily and effectively analyzed, and impurities are simultaneously improved.
  • Imatinib mesylate and impurity F are shown in the table below:
  • the inventors have explored suitable analytical conditions by repeatedly screening the chromatographic column, mobile phase, mass spectrometry and other conditions in high performance liquid chromatography-mass spectrometry.
  • the key detection conditions such as a suitable buffer solution system, the ratio of the mobile phase, and mass spectrometry were selected, and the finally established method achieved the above object.
  • the method for the analysis of imatinib mesylate impurity F is carried out by high performance liquid chromatography-mass spectrometry using 0.01% to 0.05% formic acid acetonitrile solution and ammonium formate buffer as mobile phase in octadecylsilane bonded silica gel. Gradient elution on the column.
  • the dilution used to dissolve the sample the ratio of acetonitrile to water is 20:80;
  • the ammonium formate buffer salt has a pH of 3 to 4, preferably a pH of 3.4 to 3.5;
  • the concentration of ammonium formate is from 0.6 g/L to 1.2 g/L.
  • the chromatographic conditions were as follows: the elution rate of the mobile phase was 0.8-1.2 ml/min; the column temperature was 30 ° C to 40 ° C; and the sample injection amount was 10 ⁇ l.
  • the mass spectrometry conditions are:
  • the gradient of the gradient elution in the above method is preferably:
  • the detection limit is 0.02ppm
  • the limit of quantification is 0.05ppm
  • the invention has the advantages of strong specificity, simplicity, high sensitivity and high sensitivity, and can be used for quality control of potential genotoxic impurities in imatinib mesylate and imatinib mesylate.
  • Figure 1 is a linear plot of imatinib mesylate impurity F.
  • Detecting the limit of the limit Under the conditions of this test, prepare different concentrations of impurity F reference substance, the detection limit is S/N ⁇ 3, the limit of quantification is S/N ⁇ 10, and the detection limit of impurity F is determined by injection. And the limit of quantitation, the experimental results are shown in the table below.
  • Solution stability investigation Take 125 mg of imatinib mesylate, place it in a 25 ml volumetric flask, dissolve it with water-acetonitrile (80..20) and dilute to the mark, shake it, and carry out the solution stability test. The content after 3, 8, and 24 hours. The results are shown in the table below.
  • the average content of the solution at room temperature for 24 h was 0.6 ppm, and the SD was 0.05, indicating that the solution was stable within 24 hours.
  • the impurity F content (0.0002% matrix sample concentration) as the benchmark 100%
  • accurately measure the impurity solution 1.0ml, 2.5ml, 5.0ml, and 10.0ml respectively into a 25ml volumetric flask containing the matrix sample, and mix.
  • the solution was diluted with water-acetonitrile (80..20) to prepare a solution containing impurities of 20%, 50%, 100%, and 200%, and the same method was used in parallel for 3 times as a test solution.
  • the specific preparation methods are shown in the table below.
  • W s the mass of the impurity reference (mg);
  • a u the peak area of the impurity in the test solution (excluding the impurity peak area in the matrix);
  • the method of the invention can effectively separate imatinib and impurity F, and can accurately and quickly determine imatinib impurity F.
  • the method is simple, rapid, accurate, effective and high precision, and is determined by IMA.

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  • Physics & Mathematics (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Immunology (AREA)
  • Pathology (AREA)
  • Other Investigation Or Analysis Of Materials By Electrical Means (AREA)

Abstract

L'invention concerne un procédé d'analyse haute sensibilité destiné à la détection d'impuretés génotoxiques d'imatinib. En ce qui concerne l'impureté F génotoxique d'imatinib, un procédé d'analyse a été mis au point qui utilise une combinaison d'une chromatographie liquide et d'une spectrométrie de masse très performantes, à l'aide d'un solvant organique à phase mixte et d'eau pour dissoudre un échantillon, la phase mobile étant de l'acétonitrile et du formiate d'ammonium à un pH égal à 3,5, et l'élution par gradient étant réalisée sur une colonne chromatographique de gel de silice greffé de groupes octadécyle. Le procédé de l'invention résout simplement et efficacement les problèmes de faible sensibilité et de faible spécificité liés à la détection de l'impureté F, et sépare et détecte plus efficacement l'impureté F génotoxique d'imatinib.
PCT/CN2016/111651 2016-03-11 2016-12-23 Procédé d'analyse haute sensibilité destiné à la détection d'impuretés génotoxiques d'imatinib Ceased WO2017152689A1 (fr)

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CN110687238A (zh) * 2019-11-20 2020-01-14 江苏豪森药业集团有限公司 一种甲磺酸氟马替尼有关物质的检测方法
CN111426773A (zh) * 2020-05-27 2020-07-17 上海旭东海普药业有限公司 高效液相色谱法检测盐酸胺碘酮中的碘化物杂质
CN112986432A (zh) * 2021-02-20 2021-06-18 天科(荆州)制药有限公司 一种2,4-二氨基-6-氯嘧啶有关物质的检测方法及其应用
CN113406236A (zh) * 2021-06-22 2021-09-17 海南鑫开源医药科技有限公司 1-（3-吡啶基）-3-（二甲氨基）-2-丙烯-1-酮中杂质的检测方法
CN114184699A (zh) * 2021-12-06 2022-03-15 北京悦康科创医药科技股份有限公司 液质联用测定艾司奥美拉唑钠中潜在基因毒性杂质的方法
CN114264745A (zh) * 2021-12-23 2022-04-01 重庆市食品药品检验检测研究院 甲磺酸伊马替尼有关物质及其制剂有关物质的检测方法
CN114354810A (zh) * 2022-01-04 2022-04-15 武汉九州钰民医药科技有限公司 克林霉素磷酸酯中杂质n的检测方法、及杂质的分离方法
CN114414715A (zh) * 2022-01-26 2022-04-29 武汉九州钰民医药科技有限公司 头孢他啶残留溶剂中苯的检测方法和应用
CN114414675A (zh) * 2021-12-20 2022-04-29 石家庄四药有限公司 己酮可可碱中间体中卤代烷烃类基因毒性杂质的检测方法
CN114689751A (zh) * 2022-03-30 2022-07-01 山东省食品药品检验研究院 一种烷基化类基因毒杂质的非靶向筛查方法
CN114720578A (zh) * 2021-09-16 2022-07-08 上海峰林生物科技有限公司 一种1-丙烯磷酸二乙酯杂质的检测方法
CN114814041A (zh) * 2022-06-09 2022-07-29 浙江金立源药业有限公司 一种采用液质联用仪检测替米沙坦中溴代烷烃类遗传毒性杂质的方法
CN115097026A (zh) * 2022-06-08 2022-09-23 河北常山生化药业股份有限公司 从药物中检测吡唑并嘧啶苯磺酸酯类化合物的方法
CN115128177A (zh) * 2021-06-18 2022-09-30 上药康丽（常州）药业有限公司 利用hplc法分析测定更昔洛韦缩合物中基因毒性杂质的方法
CN115201379A (zh) * 2022-07-26 2022-10-18 常州瑞明药业有限公司 非洛地平中基因毒性杂质的检测方法
CN115326937A (zh) * 2021-05-11 2022-11-11 山东省食品药品检验研究院 一种基因毒杂质捕捉用固相探针及其使用方法与应用
WO2024124423A1 (fr) * 2022-12-14 2024-06-20 山东省食品药品检验研究院 Procédé de criblage non ciblé d'impuretés génotoxiques alkylées

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CN110687238B (zh) * 2019-11-20 2022-04-19 江苏豪森药业集团有限公司 一种甲磺酸氟马替尼有关物质的检测方法
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CN112986432B (zh) * 2021-02-20 2022-08-26 天科(荆州)制药有限公司 一种2,4-二氨基-6-氯嘧啶有关物质的检测方法及其应用
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CN114354810B (zh) * 2022-01-04 2024-04-19 武汉九州钰民医药科技有限公司 克林霉素磷酸酯中杂质n的检测方法、及杂质的分离方法
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CN114814041B (zh) * 2022-06-09 2024-05-10 浙江金立源药业有限公司 一种采用液质联用仪检测替米沙坦中溴代烷烃类遗传毒性杂质的方法
CN115201379A (zh) * 2022-07-26 2022-10-18 常州瑞明药业有限公司 非洛地平中基因毒性杂质的检测方法
CN115201379B (zh) * 2022-07-26 2023-10-20 常州瑞明药业有限公司 非洛地平中基因毒性杂质的检测方法
WO2024124423A1 (fr) * 2022-12-14 2024-06-20 山东省食品药品检验研究院 Procédé de criblage non ciblé d'impuretés génotoxiques alkylées

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