CN106932522A - The assay method of impurity compound I contents in a kind of nilotinib - Google Patents
The assay method of impurity compound I contents in a kind of nilotinib Download PDFInfo
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- CN106932522A CN106932522A CN201511027252.4A CN201511027252A CN106932522A CN 106932522 A CN106932522 A CN 106932522A CN 201511027252 A CN201511027252 A CN 201511027252A CN 106932522 A CN106932522 A CN 106932522A
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- Prior art keywords
- nilotinib
- compound
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- acetonitrile
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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
- G01N30/88—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
- G01N2030/884—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 organic compounds
-
- 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
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- Health & Medical Sciences (AREA)
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- Analytical Chemistry (AREA)
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- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Other Investigation Or Analysis Of Materials By Electrical Means (AREA)
Abstract
The invention discloses the measure analysis method of 3- in a kind of nilotinib (4- methyl-1 H-imidazole-1-groups) -5- (trifluoromethyl) aniline content, the method directly determines the content of 3- (4- methyl-1 H-imidazole-1-groups) -5- (trifluoromethyl) aniline in nilotinib with HPLC-MS instrument.The analysis method is good with selectivity compared with prior art, and favorable reproducibility, sensitivity is high, is adapted to the features such as doing trace analysis.
Description
Technical field
The present invention relates to directly determine 3- (4- methyl in nilotinib with HPLC-MS instrument
- 1H- imidazoles -1- bases) -5- (trifluoromethyl) aniline (hereinafter referred to as compound I) content.The method can be preferably
Trace compound I contents in control bulk drug and preparation, are that the healthy and safe medication of patient provides safeguard, and are belonged to
Pharmaceutical technology field.
Technical background
Nilotinib, chemical name Nilotinib.
It is a kind of chronic myelogenous leukemia treated to the past treatment resistance or the Philadelphia Chromosome Positive not tolerated
(Ph+CML) medicine of chronic phase or accelerated period adult patient.Nilotinib structure is as follows：
Containing the compound I of reaction residual in nilotinib, structure is as follows：
The compound I content that accurate quantitative analysis ground determines trace in nilotinib is extremely challenging.It is difficult with gas phase,
Liquid chromatogram etc. carries out trace and directly determines to it.
At present, constant 3- (4- methyl-1 H-imidazole-1-groups) -5- (trifluoromethyl) aniline in nilotinib is only determined
Using classical chromatography, its selectivity, sensitivity, method precision and repeatability all exist the method for content
Very big defect, it is impossible to which reliable trace analysis result is provided.In order to overcome the defect of former method, the present invention to adopt
The content of compound I in nilotinib is directly determined with HPLC-MS instrument.The analysis method
With simple to operate, selectivity is good, sensitive high, favorable reproducibility the features such as.
The content of the invention
As described above, directly there are various defects in accurate quantitative analysis measure trace compound I.However with chemical combination
Thing I has stability strong and is especially suitable for the feature that reversed-phase liquid chromatography is separate, and in mass detector very
Easily the characteristics of the molecular structure of ionization and the suitable quantitative analysis with stabilization, high-efficient liquid phase color can be used
Spectrum-GC-MS is directly determined.In addition, compound I has in mass detector sensitively absorb this special
Levying greatly improves the sensitivity of this method and selectivity.
It is found by experiment that nilotinib has extraordinary dissolubility in acetonitrile.The present invention will be with acetonitrile as dilute
Release agent.
The present invention relates to a kind of measure analysis method of compound I content in nilotinib, the method is directly to use
HPLC-MS instrument determines the content of compound I in nilotinib.
With acetonitrile as dilution in above-mentioned sample preparation.
Above-mentioned use HPLC-MS instrument, cation choice ion pattern.
The method includes following steps：
(1) nilotinib raw material or powder formulation are taken, sample solution is prepared as dilution using acetonitrile solution；
(2) octadecylsilane chemically bonded silica chromatographic column is used, mobile phase is 0.05%-0.2% formic acid or acetic acid or trifluoro
Acetic acid aqueous solution and acetonitrile, carry out gradient elution.
(3) it is 0.3-1.2mL/mL to set flow rate of mobile phase, and column temperature is controlled between 25 DEG C -40 DEG C.
(4) the sample solution 5uL of step (1) is taken, sample introduction records mass spectrum total ion current figure.
(5) mass detector, ion mode selection cation is used to take the sample solution sample introduction of (1), record compound
I mass ions flow graphs.
The technical solution adopted by the present invention is as follows：
Sample pre-treatments：
Dilution：Using the acetonitrile of chromatographic grade.
Compound I standard liquids：With the accurate Compound I solution for preparing 5.7ng/ml of dilution.
Sample solution：Precision weighs 30mg samples in the volumetric flask of 10ml, is dissolved with dilution and constant volume
To scale, sample introduction.
The present invention is using chromatographic column：Octadecylsilane chemically bonded silica chromatographic column.Flow velocity 0.3-1.2mL/mL.
25 DEG C -40 DEG C of column temperature.Mobile phase A：0.05%-0.2% formic acid or acetic acid or trifluoroacetic acid aqueous solution, mobile phase
B：Acetonitrile, gradient is as follows：
| A | B | |
| 0min | 90% | 10% |
| 8min | 10% | 90% |
Mass detector：Positive ion mode, [M+H]+:242
Brief description of the drawings：
Accompanying drawing 1：The according to embodiments of the present invention 1 compound I mass spectrum rod figures for obtaining；
Accompanying drawing 2：The according to embodiments of the present invention 1 compound I standard items mass spectrum total ion current figures for obtaining；
Accompanying drawing 3：The according to embodiments of the present invention 2 nilotinib sample mass spectrum total ion current figures for obtaining；
Accompanying drawing 4：The according to embodiments of the present invention 3 nilotinib sample pipetting volume rate of recovery mass spectrum total ion current figures for obtaining.
Specific embodiment
In order to be better understood from technical scheme, make further with reference to specific embodiment of the invention
Illustrate, but it is not restricted to the present invention.
Embodiment one
Instrument and condition：
High performance liquid chromatography GC-MS：Agilent 1260 infinity, MS detectors.
Chromatographic column：Octadecylsilane chemically bonded silica chromatographic column
Mobile phase：A：0.05%-0.2% formic acid or acetic acid or trifluoroacetic acid aqueous solution B:Acetonitrile.
It is isocratic as follows：0~8.0min, organic Phase Proportion is changed into 90% from 10%.
Column temperature：35℃.
Flow velocity：1.0mL/min
Selection cation：242
Sampling volume：5ul.
Experimental procedure：
1) mobile phase A is prepared：Precision measures 1.0mL trifluoroacetic acids and is dissolved in 1000mL water, mixes.
2) dilution B：Acetonitrile
3) standard liquid C：Precision weighs about 28.5mg compounds I in 100ml volumetric flasks, plus B molten
Solution constant volume, shakes up, and precision measures 2.0ml and is placed in another 100ml volumetric flasks, plus B constant volumes, obtains final product standard
Solution C, sample introduction records mass spectrum rod figure, sees typical figure 1.Record compound I mass spectrum total ion current figures, are shown in
Typical figure 2.
Embodiment two
Instrument and condition：
High performance liquid chromatograph：Agilent 1260 infinity, MS detectors.
Chromatographic column：Octadecylsilane chemically bonded silica chromatographic column
Mobile phase：A：0.05%-0.2% formic acid or acetic acid or trifluoroacetic acid aqueous solution B:Acetonitrile.
It is isocratic as follows：0~8.0min, organic Phase Proportion is changed into 90% from 10%.
Column temperature：35℃.
Flow velocity：1.0mL/min
Selection cation：242
Sampling volume：5ul.
Experimental procedure：
1) mobile phase A is prepared：Precision measures 1.0mL trifluoroacetic acids and is dissolved in 1000mL water, mixes.
2) dilution B：Acetonitrile
3) standard liquid C：Precision weighs about 28.5mg compounds I in 100ml volumetric flasks, plus B molten
Solution constant volume, shakes up, and precision measures 2.0ml and is placed in another 100ml volumetric flasks, plus B constant volumes, obtains final product standard
Solution C.
4) sample solution D:Precision weighs about 30mg nilotinib samples and is placed in 10ml volumetric flasks, plus B
Constant volume, obtains final product sample solution D, sample introduction.Record compound I mass spectrum total ion current figures, are shown in typical figure 3.
Embodiment three
Instrument and condition：
High performance liquid chromatograph：Agilent 1260 infinity, MS detectors.
Chromatographic column：Octadecylsilane chemically bonded silica chromatographic column
Mobile phase：A：0.05%-0.2% formic acid or acetic acid or trifluoroacetic acid aqueous solution B:Acetonitrile.
It is isocratic as follows：0~8.0min, organic Phase Proportion is changed into 90% from 10%.
Column temperature：35℃.
Flow velocity：1.0mL/min
Selection cation：242
Sampling volume：5ul.
Experimental procedure：
1) mobile phase A is prepared：Precision measures 1.0mL trifluoroacetic acids and is dissolved in 1000mL water, mixes.
2) dilution B：Acetonitrile
3) standard liquid C：Precision weighs about 28.5mg compounds I in 100ml volumetric flasks, plus B molten
Solution constant volume, shakes up, and precision measures 2.0ml and is placed in another 100ml volumetric flasks, plus B constant volumes, obtains final product standard
Solution C.
4) sample solution E:Precision weighs about 30.0mg nilotinib samples, is dissolved simultaneously with standard liquid C
Scale is titrated to, is mixed, sample introduction.Record compound I mass spectrum total ion current figures, are shown in typical figure 4.
Claims (3)
1. genotoxicity impurity 3- (4- methyl-1 H-imidazole-1-groups) -5- (trifluoromethyl) aniline in a kind of nilotinib (with
Lower abbreviation compound I) content measure analysis method, it is characterised in that directly with high performance liquid chromatography-matter
Spectrum combined instrument determines the content of the compound I of trace in nilotinib.
2. analysis method according to claim 1, it is characterised in that use HPLC-MS instrument,
Ion mode selects cation.
3. according to claim 1, it is characterised in that the method includes following steps：
(1) nilotinib raw material or powder formulation are taken, sample solution is prepared as dilution using acetonitrile solution；
(2) octadecylsilane chemically bonded silica chromatographic column is used, mobile phase is 0.05%-0.2% formic acid or acetic acid or trifluoro
Acetic acid aqueous solution and acetonitrile, carry out gradient elution.
(3) it is 0.3-1.2mL/mL to set flow rate of mobile phase, and column temperature is controlled between 25 DEG C -40 DEG C.
(4) the sample solution 5uL of step (1) is taken, sample introduction records mass spectrum total ion current figure.
(5) use mass detector, ion mode selection cation takes the sample solution sample introduction of (1), record mass spectrum from
Subflow figure.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201511027252.4A CN106932522A (en) | 2015-12-31 | 2015-12-31 | The assay method of impurity compound I contents in a kind of nilotinib |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201511027252.4A CN106932522A (en) | 2015-12-31 | 2015-12-31 | The assay method of impurity compound I contents in a kind of nilotinib |
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| Publication Number | Publication Date |
|---|---|
| CN106932522A true CN106932522A (en) | 2017-07-07 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201511027252.4A Pending CN106932522A (en) | 2015-12-31 | 2015-12-31 | The assay method of impurity compound I contents in a kind of nilotinib |
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| CN (1) | CN106932522A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113419004A (en) * | 2021-06-22 | 2021-09-21 | 海南鑫开源医药科技有限公司 | Method for detecting impurities in methyl 3-amino-4-methylbenzoate |
| WO2022068876A1 (en) * | 2020-09-29 | 2022-04-07 | Shenzhen Pharmacin Co., Ltd. | Pharmaceutical compositions |
| CN115436522A (en) * | 2022-09-19 | 2022-12-06 | 上海凌凯医药科技有限公司 | Method for detecting impurity content of intermediate of Tecatinib |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100016590A1 (en) * | 2008-07-17 | 2010-01-21 | Teva Pharmaceutical Industries Ltd. | Nilotinib intermediates and preparation thereof |
| CN105738492A (en) * | 2014-12-10 | 2016-07-06 | 人福医药集团股份公司 | Method for detecting impurity content in lapatinib through combination of LC-MS and MS |
| CN105949128A (en) * | 2016-05-27 | 2016-09-21 | 浙江汇能生物股份有限公司 | Preparation method of nilotinib intermediate-3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline |
-
2015
- 2015-12-31 CN CN201511027252.4A patent/CN106932522A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100016590A1 (en) * | 2008-07-17 | 2010-01-21 | Teva Pharmaceutical Industries Ltd. | Nilotinib intermediates and preparation thereof |
| CN105738492A (en) * | 2014-12-10 | 2016-07-06 | 人福医药集团股份公司 | Method for detecting impurity content in lapatinib through combination of LC-MS and MS |
| CN105949128A (en) * | 2016-05-27 | 2016-09-21 | 浙江汇能生物股份有限公司 | Preparation method of nilotinib intermediate-3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline |
Non-Patent Citations (2)
| Title |
|---|
| G. SOWJANYA, M. MATHRUSRI ANNAPURNA, A. VENKATA SRIRAM: "Development and Validation of a Stability Indicating RP-HPLC Method for the Determination of Nilotinib (A Tyrosine Kinase Inhibitor)", 《INDO AMERICAN JOURNAL OF PHARMACEUTICAL RESEARCH》 * |
| 郝月: "5-三氟甲基-3-（4-甲基-1H-咪唑-1-基）-苯胺的合成研究", 《中国优秀硕士学位论文全文数据库》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022068876A1 (en) * | 2020-09-29 | 2022-04-07 | Shenzhen Pharmacin Co., Ltd. | Pharmaceutical compositions |
| CN113419004A (en) * | 2021-06-22 | 2021-09-21 | 海南鑫开源医药科技有限公司 | Method for detecting impurities in methyl 3-amino-4-methylbenzoate |
| CN115436522A (en) * | 2022-09-19 | 2022-12-06 | 上海凌凯医药科技有限公司 | Method for detecting impurity content of intermediate of Tecatinib |
| CN115436522B (en) * | 2022-09-19 | 2023-08-08 | 上海凌凯医药科技有限公司 | Method for detecting impurity content of criatinib intermediate |
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Application publication date: 20170707 |
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