LC-MS/MS combined method for determining impurity content in lapatinib

A technology of lapatinib and fluorobenzyloxy, applied in the field of drug analysis, can solve the problems such as no method for the determination of the content of compound 4 and compound 9 that has been reported, and the impurity content analysis and determination method needs to be improved, and the detection result is achieved. Accurate and reliable, easy to operate, easy to operate

Active Publication Date: 2017-12-19
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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  • LC-MS/MS combined method for determining impurity content in lapatinib
  • LC-MS/MS combined method for determining impurity content in lapatinib
  • LC-MS/MS combined method for determining impurity content in lapatinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0066] Use the mass spectrometer (AB Sciex Q-Trap 4500) 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 product ion with higher intensity as the final detection ion, the spectrum is shown in 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 pole

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 (Synergi Hydro-RP, 50*3.0, 4μm; Synergi Polar-RP 50*3.0, 4μm; Aquasil C1850*2.1mm, 5μm; Kromasil silica 50*3.0mm, 5μm; Betasil silica-10050 *2.1mm, 5μm), with acetonitrile as mobile phase B and water (containing 5mM 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 Aquasil C18 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] When using Betasil silica-100 column and Kromasil silica column, the retention of compound 9 was strong, but the retention of compound 4 was not.

[0078] Therefore, the present invention pr...

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: AB Sciex Q-Trap 4500,

[0083] HPLC: Shimadzu 20ACXR

[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 intermed...

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Abstract

The present invention provides a method for detecting the content of impurities, namely, 4-(3-fluorobenzyloxy)3-chlorobenzenamine and 2-aminoethylmethylsulfone hydrochloride in lapatinib by using LC-MS / MS.

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 Patents(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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