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Method for detecting impurity content in lapatinib through combination of LC-MS and MS

A technology of lapatinib and fluorobenzyloxy, applied in the field of drug analysis, can solve the problems that there is no method for determining the content of compound 4 and compound 9, which has been reported, and the method for analyzing and determining the content of impurities needs to be improved, and the detection result is achieved. Accurate and reliable, easy to operate, good repeatability

Active Publication Date: 2016-07-06
HUBEI BIO PHARMA IND TECHCAL INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] In the prior art, there is only a method for limiting the amount of impurities for compound 4, but there is currently no method for simultaneous content determination of compound 4 and compound 9. Therefore, the impurity content analysis and determination method for lapatinib still needs to be improved

Method used

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  • Method for detecting impurity content in lapatinib through combination of LC-MS and MS
  • Method for detecting impurity content in lapatinib through combination of LC-MS and MS
  • Method for detecting impurity content in lapatinib through combination of LC-MS and MS

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0066] Use a mass spectrometer (ABSciexQ-Trap4500) to perform a full scan (Q1Scan) on compound 4, compound 9, and lapatinib in positive ion mode, find the corresponding parent ion, and then do the corresponding secondary ion on the parent ion, select the intensity The higher product ions are used as the final detection ions, see the spectrum Figure 2 to Figure 5 . Finally, each compound selects an ion pair with higher intensity, and optimizes the corresponding parameters (ion source parameters, parameters related to the compound). The results are shown in Table 3 and Table 4.

[0067] Table 3: Ion source parameters

[0068] polarity positive electrode scan type MRM Curtain gas (CUR) 30psi Ion source (GS1) 50psi Ion source (GS2) 60psi ion ejection voltage 5500V temperature 550℃

[0069] Table 4: Compound-related parameters

[0070]

[0071]

Embodiment 2

[0073] Using 5 types of chromatographic columns (SynergiHydro-RP, 50*3.0, 4μm; SynergiPolar-RP50*3.0, 4μm; AquasilC1850*2.1mm, 5μm; Kromasilsilica50*3.0mm, 5μm; Betasilsilica-10050*2.1mm, 5μm), With acetonitrile as mobile phase B and water (containing 5 mM ammonium formate) as mobile phase A, compound 4 and compound 9 were detected by LC-MS / MS respectively, and the chromatograms were recorded.

[0074] result:

[0075] When Hydro-RP and Polar-RP columns were used, compound 9 was basically not retained on Hydro-RP and Polar-RP columns.

[0076] When using AquasilC18 chromatographic column, compound 9 was not retained when low organic phase (20% acetonitrile isocratic elution) was used, but compound 9 was retained in high organic phase (95% acetonitrile isocratic elution).

[0077] Compound 9 was strongly retained, but compound 4 was not, using Betasilsilica-100 and Kromasilsilica columns.

[0078] Therefore the present invention preferably adopts AquasilC18 chromatographic co...

Embodiment 3

[0079] Embodiment 3: methodological investigation and sample analysis

[0080] According to the limit of compound 4 is not higher than 4ug / 1g, the limit of compound 9 is not higher than 0.02%, the calibration range of the two compounds is respectively 0.200ng / ml-10.0ng / ml (compound 4), 10ng / ml ml—500ng / ml (compound 9). Instruments and reagents

[0081] Reagents: acetonitrile (Fisher), water, ammonium formate, lapatinib API (14 batches), 4-(3-fluorobenzyloxy)-3-chloroaniline (batch number: 120814), 2-( Thiamyl) ethylamine hydrochloride (batch number: 20120521CMQA-1-MZP-01-014).

[0082] Instrument: mass spectrometer: ABSciexQ-Trap4500,

[0083] HPLC: Shimadzu20ACXR

[0084] (1) Preparation of reference substance stock solution: Take an appropriate amount of reference substance (compound 4, compound 9) and dissolve it in a solvent (acetonitrile: water = 4:1) to prepare a 1.00 mg / ml stock solution. Then compound 4 was diluted with acetonitrile: water (1:1) to an intermediate...

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Abstract

The invention provides a method for detecting 4-(3-fluorobenzyloxy)-3-chloroaniline and 2-(methylsulfonyl) ethylamine hydrochloride impurity contents in lapatinib through combination of LC-MS and MS. According to the method, 4-(3-fluorobenzyloxy)-3-chloroaniline and 2-(methylsulfonyl) ethylamine hydrochloride impurities in a lapatinib bulk drug can be quickly and effectively detected, and the two impurity contents are subjected to quantitative detection and analysis. Through application of the method, the detection result is accurate and reliable. The method is simple to operate, is fast, and is high in specialization, good in repeatability, and is free of residual effect. The method can be used for quality control of production of a lapatinib medicine.

Description

technical field [0001] The invention relates to the technical field of drug analysis, in particular to a method for detecting the content of impurities in the antineoplastic drug lapatinib by combining LC-MS / MS. Background technique [0002] Lapatinib is a small molecule kinase inhibitor that can simultaneously target human epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor-2 (HER2), developed by GSK and obtained in March 2007 Approved by the US FDA, it is used for combination therapy: combined use of capecitabine in the treatment of advanced or metastatic breast cancer with overexpression of HER2, and combination of letrozole in the treatment of postmenopausal women with overexpression of HER2 and hormone receptor positive metastatic breast cancer. [0003] 4-(3-fluorobenzyloxy) 3-chloroaniline (compound 4) and 2-(thymphenyl) ethylamine hydrochloride (compound 9) are respectively two kinds of production uses for the preparation of lapatinib b...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): G01N30/02
CPCG01N30/02
Inventor 许勇王学海李莉娥夏亚子郭涤亮乐洋黄璐杨仲文余艳平胡斌胡虹田华冯权武朱垒肖强黄松于静
Owner HUBEI BIO PHARMA IND TECHCAL INST
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