CN104391058A - Detection method of afatinib and isomer of afatinib - Google Patents
Detection method of afatinib and isomer of afatinib Download PDFInfo
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- CN104391058A CN104391058A CN201410692721.3A CN201410692721A CN104391058A CN 104391058 A CN104391058 A CN 104391058A CN 201410692721 A CN201410692721 A CN 201410692721A CN 104391058 A CN104391058 A CN 104391058A
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- ethanol
- diethylamine
- methyl alcohol
- normal hexane
- afatinib
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Abstract
The invention relates to a liquid phase separation detection method of afatinib and enantiomer of the afatinib, and belongs to the technical field of separation detection. The method comprises the step of carrying out isocratic elution by adopting 250mm*4.6mm and 5 micrometers CHIRALPAK OZ-H chiral chromatographic column as a separation chromatographic column and adopting a mixed solution of n-hexane, ethanol, methanol and diethylamine as a flow phase. By adopting the method, the afatinib and an enantiomer impurity of the afatinib can be effectively separated and detected, and the peak pattern of a chromatographic peak is good.
Description
Technical field
The Ah method of the present invention relates to replaces a kind of HPLC method for separating and detecting of Buddhist nun and isomer impurities thereof, belongs to pharmaceutical technology sectors.
Background technology
Ah method is for Buddhist nun (Afatinib), chemistry (2E)-4-by name [(the chloro-4-fluorophenyl of 3-) is amino]-6-{ [4-(N, N-dimethylamino)-1-oxo-2-butene-1-Ji] is amino }-7-((3S)-tetrahydrofuran-3-base oxygen base)-quinazoline; It is the irreversible inhibitor of EGF-R ELISA (EGFR) and human epidermal growth factor receptor 2 (HER2) tyrosine kinase, its 2-maleate has been approved for the diseases such as treatment advanced Non-small cell lung (NSCLC), and Ah method replaces Buddhist nun's structure such as formula shown in (1):
There is a chiral carbon in Buddhist nun's structure in Ah method, has an enantiomter impurity, and detection Ah method in Buddhist nun's process, Ah method is difficult to be separated, detect with its enantiomter impurity for Buddhist nun.
Summary of the invention
Summary of the invention
The invention provides a kind of easy, effective HPLC and be separated the method for the Ah method of detection for Buddhist nun, its enantiomter impurity.
The present inventor is attempted by test of many times, by screening chromatographic column and the testing conditions such as mobile phase, flow velocity, column temperature adapted, obtain a kind of be applicable to Ah method for Buddhist nun, its enantiomter impurity method for separating and detecting, described method adopts CHIRALPAK OZ-H, 250mmX4.6mm, 5 μm, chiral chromatographic column is separation chromatography post; With normal hexane, ethanol, methyl alcohol, diethylamine mixed solution for mobile phase; Ah method effectively can be separated detection for Buddhist nun and enantiomter impurity thereof.
Term definition
During term " degree of separation " refers to that HPLC detects, the difference of adjacent chromatographic peak retention time and the ratio of the wide average of two chromatogram peak-to-peaks.
Detailed Description Of The Invention
Inventor by research, develop a kind of be separated detect Ah method for Buddhist nun, its enantiomter impurity method, method comprises: carry out on high performance liquid chromatograph, and chromatographic column is CHIRALPAK OZ-H, 250mmX4.6mm, 5 μm of chiral chromatographic columns; Mobile phase is normal hexane, ethanol, methyl alcohol and diethylamine mixed solution, and in mixed solvent, methyl alcohol and diethylamine volume ratio are 100:0.1, and the volume ratio of normal hexane, ethanol, methyl alcohol and diethylamine is 550-650:350-250:100:0.1; Column temperature is 15 DEG C-35 DEG C; Flow velocity is 0.5mL/min-1.0mL/min.
Inventor once attempted using CHIRALPAK AS-H, 4.6mmX250mm, 5 μm of chiral chromatographic columns;
iC, 4.6mmX250mm, 5 μm, chiral chromatographic column;
oD-H, 4.6mmX250mm, 5 μm of chiral chromatographic columns;
oJ-H, 4.6mmX250mm, 5 μm of chiral chromatographic columns etc. are for analyzing chromatographic column; Use the relative test sample of identical flowing to carry out analysis to detect, result shows poor for the separating effect of Buddhist nun and corresponding isomeride thereof according to Shandong in test sample of above-mentioned chromatographic column, and degree of separation is low, also can not well improve degree of separation and sensitivity at adjustment mobile phase ratio; And CHIRALPAK OZ-H, 250mmX4.6mm, the separating effect of 5 μm of chiral chromatographic columns is better.
In testing process, mobile phase or ethanol can be used to be diluting solvent.
In described detection method, operable detecting device has UV-detector.
In described detection method, the sample size of the sample of detection is 0.1 μ L-20 μ L.In some embodiments, the sample size of the sample of detection is 2 μ L-10 μ L.In some embodiments, the sample size of the sample of detection is 5 μ L.
In described detection method, detecting working time can be 15min-20min.
In some embodiments, mobile phase is normal hexane, ethanol, methyl alcohol and diethylamine mixed solution, and the volume ratio of normal hexane, ethanol, methyl alcohol and diethylamine is 550:350:100:0.1.In one embodiment, in mobile phase, the volume ratio of normal hexane, ethanol, methyl alcohol and diethylamine is 600:300:100:0.1.
In some embodiments, determined wavelength is 256nm.
In certain embodiments, the flow velocity of described mobile phase is 0.7mL/min.
In certain embodiments, described column temperature is 30 DEG C.
In certain embodiments, a kind of be separated detect Ah method for Buddhist nun, its enantiomter impurity method comprise: carry out on high performance liquid chromatograph, detecting device is UV-detector, and determined wavelength is 256nm; Chromatographic column is CHIRALPAK OZ-H, 250mmX4.6mm, 5 μm of chiral chromatographic columns; Mobile phase is normal hexane, ethanol, methyl alcohol and diethylamine mixed solution, and the volume ratio of normal hexane, ethanol, methyl alcohol and diethylamine is 600:300:100:0.1; Flow velocity is 0.6mL/min-0.8mL/min; Column temperature is 25 DEG C-35 DEG C.
In certain embodiments, a kind of be separated detect Ah method for Buddhist nun, its enantiomter impurity method comprise: carry out on high performance liquid chromatograph, detecting device is UV-detector, and determined wavelength is 256nm; Chromatographic column is CHIRALPAK OZ-H, 250mmX4.6mm, 5 μm of chiral chromatographic columns; Mobile phase is normal hexane, ethanol, methyl alcohol and diethylamine mixed solution, and the volume ratio of normal hexane, ethanol, methyl alcohol and diethylamine is 600:300:100:0.1; Flow velocity is 0.7mL/min; Sample size is 5 μ L; Column temperature is 30 DEG C; Working time is 20min.
Detection method of the present invention, Ah method effectively can be separated for Buddhist nun and enantiomter impurity thereof, degree of separation reaches 3.8, thus effectively can control the quality of Ah method for Buddhist nun.Method of the present invention can be separated the Ah method of detecting simply, fast and accurately for Buddhist nun and enantiomter impurity thereof, may be used for the quality control in producing.
Accompanying drawing explanation
Fig. 1 shows the testing result of embodiment 1 empty solution;
Fig. 2 shows that in embodiment 1, Ah method is for the testing result of Buddhist nun's sample;
Fig. 3 shows that in embodiment 2, Ah method is for the testing result of Buddhist nun's sample;
Fig. 4 shows that in embodiment 3, Ah method is for the testing result of Buddhist nun's sample;
In each figure, horizontal ordinate is the time, and ordinate is signal intensity, denotes retention time (Retention Time) and the area percentage (Area Percent) of each chromatographic peak in figure.
Embodiment
In order to make those skilled in the art understand technical scheme of the present invention better, below disclose further some non-limiting embodiments the present invention is described in further detail.
Reagent used in the present invention all can be buied from the market or can be obtained by method described in the invention preparation.
In the present invention, g represents gram, and mL represents milliliter, and nm represents nanometer, μm represents micron, and mm represents millimeter, and min represents minute.
Embodiment 1
Testing conditions:
Instrument: Agilent high performance liquid chromatograph, Agilent DAD UV-detector, determined wavelength: 256nm;
Chromatographic column: CHIRALPAK OZ-H, 250mmX4.6mm, 5 μm of chiral chromatographic columns;
Thinning agent: the mixed solution of normal hexane, ethanol, methyl alcohol and diethylamine, volume ratio is 600:300:100:0.1;
Mobile phase: the mixed solution of normal hexane, ethanol, methyl alcohol and diethylamine, volume ratio is 600:300:100:0.1;
Flow velocity: 0.7mL/min;
Column temperature: 30 DEG C;
Sample size: 5 μ L;
Detecting step:
The Ah method of getting is about 15mg for Buddhist nun's crude product, accurately weighed to the brown measuring bottle of 10mL, dissolves and is diluted to scale, shaking up, as need testing solution with thinning agent.
Get blank solution and need testing solution respectively, carry out detection by above-mentioned condition and analyze, record chromatogram, the results are shown in Figure 1, Fig. 2.In Fig. 2, the retention time chromatographic peak of 9.49 minutes is the chromatographic peak of Ah method for Buddhist nun; The chromatographic peak of 11.48 minutes is the enantiomeric impurity of Ah method for Buddhist nun.Degree of separation is 3.8.
Embodiment 2
Testing conditions:
Instrument: Agilent high performance liquid chromatograph, Agilent DAD UV-detector, determined wavelength: 256nm;
Chromatographic column: CHIRALPAK OZ-H, 250mmX4.6mm, 5 μm of chiral chromatographic columns;
Thinning agent: the mixed solution of normal hexane, ethanol, methyl alcohol and diethylamine, volume ratio is 600:300:100:0.1;
Mobile phase: the mixed solution of normal hexane, ethanol, methyl alcohol and diethylamine, volume ratio is 600:300:100:0.1;
Flow velocity: 0.7mL/min;
Column temperature: 25 DEG C;
Sample size: 5 μ L;
Detecting step:
The Ah method of getting is about 10mg for Buddhist nun, accurately weighed in the brown volumetric flask of 10mL, is diluted to scale, shakes up, as need testing solution with thinning agent ultrasonic dissolution.
Get need testing solution, carry out efficient liquid phase chromatographic analysis according to testing conditions, record chromatogram, the results are shown in Figure 3.
Fig. 3 proves, Ah method reaches bulk drug requirement for the optical purity of Buddhist nun, and this law may be used for the quality monitoring of Ah method for Buddhist nun.
Embodiment 3
Testing conditions:
Instrument: Agilent high performance liquid chromatograph, Agilent DAD UV-detector, determined wavelength: 256nm;
Chromatographic column: CHIRALPAK OZ-H, 250mmX4.6mm, 5 μm of chiral chromatographic columns;
Thinning agent: ethanol;
Mobile phase: the mixed solution of normal hexane, ethanol, methyl alcohol and diethylamine, volume ratio is 600:300:100:0.1;
Flow velocity: 0.7mL/min;
Column temperature: 30 DEG C;
Sample size: 5 μ L;
Detecting step:
The Ah method of getting is appropriate for Buddhist nun's sheet, and be about equivalent to Ah method for Buddhist nun 10mg, put in the brown volumetric flask of 10ml, add thinning agent ultrasonic dissolution and be diluted to scale, shaking up, filter, filtrate is as need testing solution.Get need testing solution, carry out efficient liquid phase chromatographic analysis according to testing conditions, the results are shown in Figure 4.
Method of the present invention is described by preferred embodiment, and related personnel obviously can change methods and applications as herein described or suitably change and combination in content of the present invention, spirit and scope, realizes and applies the technology of the present invention.Those skilled in the art can use for reference present disclosure, and suitable improving technique parameter realizes.Special needs to be pointed out is, all similar replacements and change apparent to those skilled in the art, they are all deemed to be included in the present invention.
Claims (6)
1. be separated the method for the Ah method of detection for Buddhist nun, comprise: on high performance liquid chromatograph, carry out degree such as grade detect, chromatographic column is CHIRALPAK OZ-H, 250mm X 4.6mm, 5 μm of chiral chromatographic columns; Mobile phase is normal hexane, ethanol, methyl alcohol and diethylamine mixed solution, and the volume ratio of normal hexane, ethanol, methyl alcohol and diethylamine is 550-650:350-250:100:0.1; Flow velocity is 0.5mL/min-1.0mL/min; Column temperature is 15 DEG C-35 DEG C.
2. method according to claim 1, detecting device is UV-detector, and determined wavelength is 256nm.
3. method according to claim 1, the sample size of the sample of detection is 0.1 μ L-20 μ L.
4. method according to claim 1, the flow velocity of described mobile phase is 0.7mL/min.
5. method according to claim 1, the volume ratio of normal hexane, ethanol, methyl alcohol and diethylamine is 600:300:100:0.1.
6., according to the arbitrary described method of claim 1-5, high performance liquid chromatograph carries out degree such as grade and detects, chromatographic column is CHIRALPAK OZ-H, 250mm X 4.6mm, 5 μm; Detecting device is UV-detector, and determined wavelength is 256nm; Mobile phase is normal hexane, ethanol, methyl alcohol and diethylamine mixed solution, and the volume ratio of normal hexane, ethanol, methyl alcohol and diethylamine is 600:300:100:0.1; Flow velocity is 0.7mL/min; Sample size is 2 μ L-10 μ L; Column temperature is 30 DEG C; Working time is 20min.
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105424842A (en) * | 2015-12-29 | 2016-03-23 | 河北神威药业有限公司 | Method for detecting Afatinib and relevant substances thereof |
| CN105588893A (en) * | 2015-12-09 | 2016-05-18 | 北京科莱博医药开发有限责任公司 | Method for detecting afatinib-dimaleate-related substances through high performance liquid chromatography |
| CN105717226A (en) * | 2016-02-02 | 2016-06-29 | 北京科莱博医药开发有限责任公司 | Method for detecting afatinib dimaleate isomers and main degradation impurities through high performance liquid chromatography |
| CN106290620A (en) * | 2016-07-31 | 2017-01-04 | 合肥远志医药科技开发有限公司 | A kind of detection method of Afatinib crude drug isomer |
| CN106442793A (en) * | 2016-10-21 | 2017-02-22 | 河北神威药业有限公司 | Method for preparing and detecting intermediate and corresponding isomer of afatinib |
| CN107490631A (en) * | 2016-06-10 | 2017-12-19 | 山东新时代药业有限公司 | A kind of analyzing detecting method of afatinib intermediate |
| CN107764907A (en) * | 2016-08-22 | 2018-03-06 | 广东东阳光药业有限公司 | The method for determining the content of Ao Gelieting enantiomters in Ao Gelieting bulk drugs |
| CN110590682A (en) * | 2019-10-14 | 2019-12-20 | 重庆医科大学 | Method for preparing afatinib impurity and prepared impurity |
| CN112110901A (en) * | 2019-06-20 | 2020-12-22 | 鲁南制药集团股份有限公司 | Preparation method of Afatinib oxidized impurities |
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Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105588893A (en) * | 2015-12-09 | 2016-05-18 | 北京科莱博医药开发有限责任公司 | Method for detecting afatinib-dimaleate-related substances through high performance liquid chromatography |
| CN105424842A (en) * | 2015-12-29 | 2016-03-23 | 河北神威药业有限公司 | Method for detecting Afatinib and relevant substances thereof |
| CN105717226A (en) * | 2016-02-02 | 2016-06-29 | 北京科莱博医药开发有限责任公司 | Method for detecting afatinib dimaleate isomers and main degradation impurities through high performance liquid chromatography |
| CN107490631A (en) * | 2016-06-10 | 2017-12-19 | 山东新时代药业有限公司 | A kind of analyzing detecting method of afatinib intermediate |
| CN106290620A (en) * | 2016-07-31 | 2017-01-04 | 合肥远志医药科技开发有限公司 | A kind of detection method of Afatinib crude drug isomer |
| CN106290620B (en) * | 2016-07-31 | 2019-02-15 | 南京臣功制药股份有限公司 | A kind of detection method of Afatinib bulk pharmaceutical chemicals isomers |
| CN107764907A (en) * | 2016-08-22 | 2018-03-06 | 广东东阳光药业有限公司 | The method for determining the content of Ao Gelieting enantiomters in Ao Gelieting bulk drugs |
| CN106442793A (en) * | 2016-10-21 | 2017-02-22 | 河北神威药业有限公司 | Method for preparing and detecting intermediate and corresponding isomer of afatinib |
| CN106442793B (en) * | 2016-10-21 | 2019-05-24 | 河北神威药业有限公司 | A kind of detection method of the intermediate for preparing Afatinib and its enantiomter |
| CN112110901A (en) * | 2019-06-20 | 2020-12-22 | 鲁南制药集团股份有限公司 | Preparation method of Afatinib oxidized impurities |
| CN110590682A (en) * | 2019-10-14 | 2019-12-20 | 重庆医科大学 | Method for preparing afatinib impurity and prepared impurity |
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