WO2016090730A1 - Procédé pour déterminer la teneur en impuretés du lapatinib par lc-ms/ms - Google Patents

Procédé pour déterminer la teneur en impuretés du lapatinib par lc-ms/ms Download PDF

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WO2016090730A1
WO2016090730A1 PCT/CN2015/070901 CN2015070901W WO2016090730A1 WO 2016090730 A1 WO2016090730 A1 WO 2016090730A1 CN 2015070901 W CN2015070901 W CN 2015070901W WO 2016090730 A1 WO2016090730 A1 WO 2016090730A1
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compound
solution
mobile phase
lapatinib
internal standard
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PCT/CN2015/070901
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Chinese (zh)
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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
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湖北生物医药产业技术研究院有限公司
人福医药集团股份公司
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Publication of WO2016090730A1 publication Critical patent/WO2016090730A1/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

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  • the invention relates to the technical field of pharmaceutical analysis, in particular to a method for detecting the impurity content of the antitumor drug lapatinib by LC-MS/MS.
  • Lapatinib is a small molecule kinase inhibitor capable of targeting both human epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor-2 (HER2), developed by GSK and acquired in March 2007. Approved by the US FDA for combination therapy: combined with capecitabine for the treatment of advanced or metastatic breast cancer overexpressing HER2, combined with letrozole for the treatment of menopausal women with metastatic breast cancer overexpressing HER2 and hormone receptors.
  • EGFR human epidermal growth factor receptor
  • HER2 human epidermal growth factor receptor-2
  • an object of the present invention is to provide an LC-MS/MS (liquid chromatography--accurate, reliable, simple, rapid, specific, and reproducible method for simultaneous quantitative analysis of the contents of Compound 4 and Compound 9. Mass spectrometry/mass spectrometry combined detection method for quality control of lapatinib drug production.
  • the inventor limits the content of the impurity of the compound 4 to not more than 4 ⁇ g / 1 g (ie, 4 ppm), and the content of the impurity of the compound 9 is not more than 0.02%, the ordinary high-efficiency liquid
  • the detection limit of Compound 4 detected by phase chromatography was very low, and only impurities of 0.1% or more were measured.
  • Compound 9 could not be measured in the liquid phase because it had no UV absorption.
  • the inventors attempted to use evaporative light scattering, although it was detectable, but the detection limit was very low, and only impurities of 2% or more were measured.
  • the organic phase (B) is acetonitrile and the aqueous phase (A) is Water (containing 5 mM ammonium formate), the injection volume is 5.00 ⁇ L, the typical chromatogram is shown in Figure 1, the peak of lapatinib, compound 4, compound 9 and lidocaine (internal standard) The times were 2.09 min, 0.54 min, 0.81 min, and 1.21 min, respectively. Due to the high concentration of the drug substance, it was switched to the waste bottle through a six-way valve from 1.5 minutes to avoid affecting the mass spectrometer.
  • the present invention provides a method for detecting the impurity content of 4-(3-fluorobenzyloxy) 3-chloroaniline and 2-(methylsulfonyl)ethylamine hydrochloride in lapatinib. According to an embodiment of the invention, the method is carried out using a LC-MS/MS combined detection method.
  • the chromatographic conditions are: the column is octadecyl bonded silica as a filler; the mobile phase is composed of a mobile phase A and a mobile phase B, wherein the mobile phase A is an aqueous solution of ammonium formate, The mobile phase B is acetonitrile; the elution mode is gradient elution.
  • the compound 4 and the compound 9 in the lapatinib bulk drug can be quantitatively detected at the same time, and both the compound 4 and the compound 9 are well retained, and the operation is simple, convenient and quick.
  • the chromatographic conditions are: octadecyl bonded silica as a filler; the mobile phase consists of mobile phase A and mobile phase B, wherein the mobile phase A is at a concentration of 5 mmol/
  • the aqueous solution of ammonium formate is used, the mobile phase B is acetonitrile; the flow rate is 0.5 ml/min to 0.7 ml/min; the column temperature is 25 degrees Celsius to 35 degrees Celsius; the injection amount is 5 ⁇ l, the detection wavelength is 261 nm, and the elution mode is gradient elution.
  • the method of the invention can quickly and effectively detect impurities in the lapatinib bulk drug, and can simultaneously quantitatively analyze the compound 4 and the compound 9, the detection result is accurate and reliable, the operation is simple, rapid, and the specificity is strong. , repeatability is good.
  • the mass spectrometry condition is: the ion source is an ESI source, and the MRM mode is monitored by positive ion mode detection and multiple reaction; the detected ion pair of lapatinib is m/z 581-365; 4-(3 - fluorobenzyloxy) 3-chloroaniline detection ion pair is m / z 252 - 143; 2- (methylsulfonyl) ethylamine detection ion pair is m / z 124 - 79; and lidocaine detection
  • the ion pair is m/z 235-86; the ion source parameters are: gas curtain gas (CUR) 30 psi; ion spray voltage (IS) 5500 V; temperature (TEM) 550 ° C; ion source GS1 50 psi; ion source GS2 260 psi.
  • the column temperature of the column is between 25 degrees Celsius and 35 degrees Celsius. Therefore, it is advantageous to simultaneously quantitatively analyze the compound 4 and the compound 9, and the detection effect is too high or too low.
  • the flow rate of the mobile phase is from 0.5 ml/min to 0.7 ml/min.
  • the concentration of the ammonium formate is 5 mmol/liter.
  • the separation effect of the compound 4, the compound 9 and the lapatinib is good, the specificity is strong, and the detection accuracy is high.
  • the conditions for the gradient elution are:
  • Compound 4 Compound 9 and Lapatinib have no residual effects, and the detection results are accurate and sensitive.
  • the column is a C18 column, preferably the column is a Thermo aquasil C18 (50*2.1 mm, 5 ⁇ m) HPLC column.
  • both Compound 4 and Compound 9 have good retention, and can quantitatively analyze Compound 4 and Compound 9 at the same time, and the operation is simple, the accuracy is high, and the repeatability is good.
  • the method of the invention comprises the following steps:
  • Chromatographic conditions octadecyl-bonded silica gel as a filler; the mobile phase A is an aqueous solution of ammonium formate at a concentration of 5 mmol/liter, and the mobile phase B is acetonitrile; the flow rate is 0.5 ml/min ⁇ 0.7ml/min; column temperature 25 degrees Celsius to 35 degrees Celsius; injection volume 5 ⁇ l, detection wavelength 261nm, gradient elution according to the following table:
  • the ion source is the ESI source, and the MRM mode is monitored by positive ion detection and multiplex reaction;
  • the detection ion pair of 4-(3-fluorobenzyloxy)-3-chloroaniline is m/z: 252 -143;
  • 2-(methylsulfonyl)ethylamine detection ion pair is m / z: 124 - 79;
  • lidocaine internal standard detection ion pair is m / z: 235 - 86;
  • the ion source parameters are:
  • the inventors have found that by using the method of the present invention, the compound 4 and the compound 9 can be quantitatively analyzed at the same time, thereby limiting the impurities in the lapatinib bulk drug, and the operation is simple, the sensitivity is high, the repeatability is good, and the specificity is Strong.
  • the standard curve method comprises the following steps:
  • the lidocaine internal standard was dissolved in an acetonitrile-water solution with a volume ratio of 1:1 to obtain an internal standard stock solution with a lidocaine internal standard concentration of 0.200 mg/mL, and the internal standard stock was also diluted.
  • Compound 4 and Compound 9 can be quantitatively and accurately quantified, accurate, reliable, simple and convenient.
  • the method for detecting impurities in the antitumor drug lapatinib by the LC-MS/MS according to the present invention can quickly and effectively detect the impurities of the compound 4 and the compound 9 in the lapatinib bulk drug, and can simultaneously quantify The contents of Compound 4 and Compound 9 were analyzed and analyzed.
  • the LC-MS/MS combined detection and analysis method described in the invention has the advantages of accurate and reliable detection, simple and convenient operation, high specificity, good repeatability and no residual effect.
  • the method for determining the impurity content of lapatinib by the LC-MS/MS combination of the present invention can be used for quality control of lapatinib drug production.
  • Figure 1 shows a typical chromatogram of lapatinib, compound 4, compound 9 and internal standard lidocaine peak time
  • Figure 3 shows a secondary mass spectrum of Compound 4 in accordance with an embodiment of the present invention
  • Figure 4 shows a secondary mass spectrum of compound 9 in accordance with an embodiment of the invention.
  • Figure 5 shows a secondary mass spectrum of lapatinib according to an embodiment of the invention
  • Figure 6 shows a chromatogram of the specificity of Compound 4 (10.0 ng/ml) in accordance with an embodiment of the present invention
  • Figure 7 shows a chromatogram of the specificity of Compound 9 (500 ng/ml) in accordance with an embodiment of the present invention
  • Figure 8 shows a chromatogram of the specificity of the internal standard lidocaine (1.00 ng/ml) in accordance with an embodiment of the present invention
  • Figure 9 shows a residual effect chromatogram of Compound 4 and Compound 9 in accordance with an embodiment of the present invention.
  • polarity positive electrode Scan type MRM Air curtain gas 30psi Ion source (GS1) 50psi Ion source (GS2) 60psi Ion jet voltage 5500V temperature 550 ° C
  • the present invention preferably employs an Aquasil C18 column.
  • the limit of compound 4 is not higher than 4 ug / 1g
  • the limit of compound 9 is not higher than 0.02%
  • the calibration range of the two compounds is 0.200 ng / ml - 10.0 ng / ml (compound 4), 10 ng / Ml-500 ng/ml (compound 9).
  • Reagents acetonitrile (Fisher), water, ammonium formate, lapatinib bulk drug (14 batches), 4-(3-fluorobenzyloxy)-3-chloroaniline (batch number: 120814), 2-( Methylsulfonyl)ethylamine hydrochloride (batch number: 20120521CMQA-1-MZP-01-014).
  • Standard curve samples were prepared according to Table 5.
  • a standard curve sample was prepared according to Table 5, and the ratio of the peak area of the analyte to the peak area of the internal standard was plotted on the ordinate, and the concentration of the analyte was plotted on the abscissa, and a linear regression operation was performed.
  • the two compounds of Compound 4 and Compound 9 have a good linear relationship in the corresponding range.
  • the quality control samples were prepared according to Table 6. Three concentrations were prepared for each concentration, and the accuracy and precision (intraday) were examined. The results are shown in Table 8. According to the results, the accuracy of Compound 4 and Compound 9 was between 85% and 115%, and the precision RSD was in the range of ⁇ 15%.
  • Specificity refers to the method used to accurately determine the characteristics of the measured object under the conditions that other components may exist.
  • compound 4 and compound 9 were simultaneously determined. According to Fig. 6 to Fig. 8, there was no compound 4 (10.0 ng/ml), compound 9 (500 ng/ml) and internal standard lidocaine (1.00 ng/ml). Interfere with each other.
  • Reagents acetonitrile (Fisher), water, ammonium formate, lapatinib bulk drug (3 batches), 4-(3-fluorobenzyloxy)-3-chloroaniline (compound 4 batch number: CM1101-130501- F1), 2-(methylsulfonyl)ethylamine hydrochloride (Compound 9 batch number: CM1101-130801-F1).
  • the chromatographic conditions and system suitability test were carried out using octadecyl bonded silica as a filler; the mobile phase consisted of mobile phase A and mobile phase B, wherein the mobile phase A was an ammonium formate aqueous solution having a concentration of 5 mmol/liter.
  • the mobile phase B is acetonitrile; the flow rate is 0.6 ml/min; the column temperature is 30 degrees Celsius; the injection amount is 5 ⁇ l, the detection wavelength is 261 nm, and the elution mode is gradient elution. Gradient elution according to Table 10 below:
  • the experiment was carried out in series with a triple quadrupole mass spectrometer, and the MRM mode was monitored by multiple reaction: the detected ion pair of the impurity to be tested 4-(3-fluorobenzyloxy)-3-chloroaniline was m/z: 252-143; The detection ion pair of 2-(methylsulfonyl)ethylamine is m/z: 124-79; the detection ion pair of lidocaine internal standard is m/z: 235-86; typical mass spectrometer detector parameters are as follows:
  • the limit of compound 4 is not higher than 4 ⁇ g / 1g
  • the limit of compound 9 is not higher than 0.02%
  • the calibration range of the two compounds is 0.200 ng / mL - 10.0 ng / mL (compound 4), 10.0 ng /mL - 500 ng / mL (compound 9).
  • the mixed intermediate solution 1 in (2) is diluted 100 times to make 100 ng / mL of compound 4, 5000 ng / mL of the compound in the mixed intermediate solution 2;
  • Standard curve samples were prepared according to Table 11.
  • test sample Weigh the appropriate amount of this product (batch number: LT20140902), accurately weighed, prepare 5.00mg/mL stock solution with acetonitrile: water (4:1), and then use acetonitrile: water (1 : 1) Dilute to 0.500 mg / mL of the solution to be tested (with internal standard 1.00 ng / mL).
  • the peak area and internal standard peak of compound 4 and compound 9 are determined by injection analysis.
  • the area ratio is calculated by substituting into the standard curve to obtain the concentrations of the compound 4 and the compound 9 in the sample (raw drug).
  • the content of the two impurities in each batch of the drug substance is then calculated.
  • the compound 4 does not exceed 4 ⁇ g / 1 g, and the compound 9 does not exceed 0.02%.
  • the calculation results are shown in Table 12. In the three batches of the lapatinib bulk drug product, the compound 4 and the compound 9 are within the limits.
  • Reagents acetonitrile (Fisher), water, ammonium formate, lapatinib bulk drug (3 batches), 4-(3-fluorobenzyloxy)-3-chloroaniline (compound 4 batch number: CM1101-130701- F2), 2-(methylsulfonyl)ethylamine hydrochloride (Compound 9 batch number: CM1101-130901-F2).
  • the chromatographic conditions and system suitability test were carried out using octadecyl bonded silica as a filler; the mobile phase consisted of mobile phase A and mobile phase B, wherein the mobile phase A was an ammonium formate aqueous solution having a concentration of 5 mmol/liter.
  • the mobile phase B is acetonitrile; the flow rate is 0.5 ml/min; the column temperature is 25 degrees Celsius; the injection amount is 5 ⁇ l, the detection wavelength is 261 nm, and the elution mode is gradient elution. Gradient elution according to Table 13 below:
  • the experiment was carried out in series with a triple quadrupole mass spectrometer, and the MRM mode was monitored by multiple reaction: the detected ion pair of the impurity to be tested 4-(3-fluorobenzyloxy)-3-chloroaniline was m/z: 252-143; The detection ion pair of 2-(methylsulfonyl)ethylamine is m/z: 124-79; the detection ion pair of lidocaine internal standard is m/z: 235-86; typical mass spectrometer detector parameters are as follows:
  • Reagents acetonitrile (Fisher), water, ammonium formate, lapatinib bulk drug (4 batches), 4-(3-fluorobenzyloxy)-3-chloroaniline (compound 4 batch number: CM1101-130701- F2), 2-(methylsulfonyl)ethylamine hydrochloride (Compound 9 batch number: CM1101-130901-F2).
  • the chromatographic conditions and system suitability test were carried out using octadecyl bonded silica as a filler; the mobile phase consisted of mobile phase A and mobile phase B, wherein the mobile phase A was an ammonium formate aqueous solution having a concentration of 5 mmol/liter.
  • the mobile phase B is acetonitrile; the flow rate is 0.7 ml/min; the column temperature is 35 degrees Celsius; the injection amount is 5 ⁇ l, the detection wavelength is 261 nm, and the elution mode is gradient elution. Gradient elution according to Table 15 below:
  • the experiment was carried out in series with a triple quadrupole mass spectrometer, and the MRM mode was monitored by multiple reaction: the detected ion pair of the impurity to be tested 4-(3-fluorobenzyloxy)-3-chloroaniline was m/z: 252-143; The detection ion pair of 2-(methylsulfonyl)ethylamine is m/z: 124-79; the detection ion pair of lidocaine internal standard is m/z: 235-86; typical mass spectrometer detector parameters are as follows:

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Abstract

La présente invention concerne un procédé pour détecter la teneur en impuretés, à savoir en 4-(3-fluorobenzyloxy)3-chlorobenzènamine et chlorhydrate de 2-aminoéthylméthylsulfone, du lapatinib par LC-MS/MS.
PCT/CN2015/070901 2014-12-10 2015-01-16 Procédé pour déterminer la teneur en impuretés du lapatinib par lc-ms/ms WO2016090730A1 (fr)

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CN112782296B (zh) * 2020-12-24 2023-01-20 上海微谱检测科技集团股份有限公司 一种采用液质连用仪检测抗癌药中浸出物的方法
CN112903856A (zh) * 2021-01-22 2021-06-04 青岛农业大学 一种用于检测水样中微量氯甲酰化合物的前处理方法及其应用
CN112903856B (zh) * 2021-01-22 2023-02-17 青岛农业大学 一种用于检测水样中微量氯甲酰化合物的前处理方法及其应用
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CN116106455A (zh) * 2023-03-28 2023-05-12 上海赛默罗生物科技有限公司 取代的烟酰胺类药物中有关物质的检测方法
CN116297974A (zh) * 2023-03-30 2023-06-23 中国人民解放军军事科学院军事医学研究院 一种同时检测血浆中利多卡因及其代谢物megx和沙丁胺醇浓度的方法
CN116626145A (zh) * 2023-07-03 2023-08-22 军科正源（北京）药物研究有限责任公司 基于多反应监测的蛋氨酸亚氨基代砜的定量检测方法
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