CN104407067B - The detection method of Buddhist nun and isomeride thereof is replaced according to Shandong - Google Patents
The detection method of Buddhist nun and isomeride thereof is replaced according to Shandong Download PDFInfo
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- CN104407067B CN104407067B CN201410655552.6A CN201410655552A CN104407067B CN 104407067 B CN104407067 B CN 104407067B CN 201410655552 A CN201410655552 A CN 201410655552A CN 104407067 B CN104407067 B CN 104407067B
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- shandong
- buddhist nun
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Abstract
The present invention relates to a kind of liquid phase separation detection method replacing Buddhist nun and enantiomter impurity thereof according to Shandong, belong to separation detection technique field.Described detection method comprises: adopt
Description
Technical field
The invention belongs to pharmaceutical technology sectors, be specifically related to be separated detection method for a kind of high-efficient liquid of Buddhist nun and isomer impurities thereof according to Shandong.
Background technology
According to Shandong for Buddhist nun (Ibrutinib), chemistry 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3 by name, 4-d] pyrimidine-1-base]-1-piperidyl]-2-propylene-1-ketone, its structure is such as formula shown in (1); A kind of irreversible bruton's tyrosine kinase (BTK, Bruton'styrosinekinase) inhibitor, the propagation of malignant B cell, existence can be suppressed, can be used for the diseases such as treatment chronic lymphocytic leukemia (CLL) and cellule lymphocytic lympboma:
There is a chiral carbon according to Shandong in Buddhist nun's structure, there is an enantiomter impurity, replace in Buddhist nun's process in detection according to Shandong, be difficult to be separated, detect with its enantiomter impurity for Buddhist nun according to Shandong.
Summary of the invention
Summary of the invention
The invention provides a kind of easy, effective HPLC and detect the method being separated and replacing Buddhist nun and enantiomter impurity thereof according to Shandong.
The present inventor is attempted by test of many times, screening chromatographic column and the testing conditions such as mobile phase, flow velocity, column temperature adapted, and obtains a kind of being applicable to according to the method for separating and detecting of Shandong for Buddhist nun, its enantiomter impurity.Final discovery adopts
aD-H, 4.6mmX250mm, 5 μm, chromatographic column is separation chromatography post, with normal hexane, ethanol for mobile phase, effectively can be separated detection by according to Shandong 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, develops a kind of separation, detects according to the method for Shandong for Buddhist nun, its enantiomter impurity, by using specific chromatographic column and controlling other testing conditions, can effectively be separated according to Shandong for Buddhist nun and enantiomter impurity thereof.
Be separated and detect according to the method for Shandong for Buddhist nun, it comprises: detect on high performance liquid chromatograph, and chromatographic column is
aD-H, 4.6mmX250mm, 5 μm, chiral chromatographic column; Mobile phase is the mixed solvent of alkane solvent and alcoholic solvent, and the volume ratio of alkane solvent and alcoholic solvent is 35:65; Column temperature is 25 DEG C-40 DEG C; Flow velocity is 0.3mL/min-0.9mL/min.
Inventor once attempted using
iC, 4.6mmX250mm, 5 μm, chiral chromatographic column, CHIRALPAKAS-H, 4.6mmX250mm, 5 μm of chiral chromatographic columns,
oD-H, 4.6mmX250mm, 5 μm, chiral chromatographic column,
oJ-H, 4.6mmX250mm, 5 μm, chiral chromatographic columns etc., for analyzing chromatographic column, use the mixed solvent of alkane solvent and alcoholic solvent to carry out to test sample analysiss and detect, and result shows above-mentioned chromatographic column to replacing the separating effect of Buddhist nun and corresponding isomeride thereof poor according to Shandong in test sample, degree of separation is low, and peak width is larger, sensitivity compares poor, also can not well improve degree of separation and sensitivity regulating the ratio of alkane solvent and alcoholic solvent; And
aD-H, 4.6mmX250mm, the separating effect of 5 μm of chromatographic columns is better.
Inventor also finds, except the selectivity of chromatographic column, alkane solvent has larger impact with the ratio of alcoholic solvent to replacing the detection that is separated of Buddhist nun and enantiomter thereof according to Shandong, the ratio of alcoholic solvent is too low, (alkane: alcohol=60:40 when being low to moderate 40%, V/V), chromatographic peak appearance time crosses slow and peak shape is not good, is unsuitable for analyzing and detects test sample; Inventor, through repeatedly attempting, finds the volume ratio of alkane solvent and alcoholic solvent to be decided to be 35:65, is conducive to detecting according to the separation of Shandong for Buddhist nun and corresponding isomeride thereof.
Before detection, sample thinning agent to be detected need be diluted.Described thinning agent is the mixed solvent of alkane solvent and alcoholic solvent, and in thinning agent, the volume ratio of alkane solvent and alcoholic solvent is 45:55-75:25.Before detection sample introduction, sample thinning agent can be mixed with the solution of 0.3mg/mL-5mg/mL, then sample detection.
Described alkane solvent is normal hexane, normal heptane, n-pentane, or its combination.Described alcoholic solvent is ethanol, isopropyl alcohol, n-propanol, or its combination.
In described detection method, spendable detecting device has UV-detector, and determined wavelength is 230nm-270nm.
In described detection method, the sample size of sample is 1 μ L-100 μ L; Working time is 40min-50min.
In some embodiments, described mobile phase is normal hexane and ethanol, and the volume ratio of normal hexane and ethanol is 35:65.
In some embodiments, thinning agent is normal hexane and ethanol, and the volume ratio of normal hexane and ethanol is 50:50.
In some embodiments, column temperature is 35 DEG C.
In some embodiments, flow velocity is 0.5mL/min.
In some embodiments, a kind of separation is detected according to the method for Shandong for Buddhist nun, and it comprises: detect on high performance liquid chromatograph, and chromatographic column is
aD-H, 4.6mmX250mm, 5 μm, chiral chromatographic column; Mobile phase is the mixed solvent of normal hexane and ethanol, and the volume ratio of normal hexane and ethanol is 35:65; Column temperature is 35 DEG C; Flow velocity is 0.5mL/min; Thinning agent is normal hexane and ethanol, and the volume ratio of normal hexane and ethanol is 50:50; Sample size is 10 μ L.
Of the present invention separation is detected according to the method for Shandong for Buddhist nun, and can simply, fast, accurately effectively will be separated with its enantiomter impurity for Buddhist nun according to Shandong, degree of separation reaches more than 5, complete baseline separation; Thus can control accurately and efficiently, according to the quality of Shandong for Buddhist nun, to can be used in production.
Accompanying drawing explanation
Fig. 1 shows the testing result of embodiment 1 empty solution;
Fig. 2 shows in embodiment 1 according to the testing result of Shandong for Buddhist nun's sample;
Fig. 3 shows in embodiment 2 according to the testing result of Shandong for Buddhist nun's sample;
Fig. 4 shows in embodiment 3 according to the testing result of Shandong for Buddhist nun's sample.
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, mg represents milligram, and mL represents milliliter, and nm represents nanometer, and mm represents millimeter, and μm expression micron, μ L represents microlitre, and mL/min represents ml/min.
Embodiment 1
Testing conditions:
Instrument: Agilent high performance liquid chromatograph, AgilentDAD UV-detector, determined wavelength: 258nm;
Chromatographic column:
aD-H, 4.6mmX250mm, 5 μm, chiral chromatographic column;
Thinning agent: normal hexane and alcohol mixeding liquid, volume ratio is 50:50;
Mobile phase: normal hexane and alcohol mixeding liquid, volume ratio is 35:65;
Flow velocity: 0.5mL/min;
Column temperature: 35 DEG C;
Sample size: 10 μ L;
Detecting step:
Get and be about 25mg according to Shandong for Buddhist nun's sample body, accurately weighed to the brown measuring bottle of 50mL, dissolve with thinning agent and be diluted to scale, shaking up, as need testing solution.Get blank solution and need testing solution respectively, carry out efficient liquid phase chromatographic analysis by above-mentioned condition, record chromatogram, result is shown in Fig. 1, Fig. 2 respectively.In Fig. 2, the retention time chromatographic peak of 20.97 minutes is for Buddhist nun's chromatographic peak according to Shandong; The chromatographic peak of 28.81 minutes is for Buddhist nun's enantiomter impurity chromatographic peak according to Shandong.
Embodiment 2
Testing conditions:
Instrument: Agilent high performance liquid chromatograph, AgilentDAD UV-detector;
Determined wavelength: 258nm;
Chromatographic column:
aD-H, 4.6mmX250mm, 5 μm, chiral chromatographic column;
Thinning agent: normal hexane and alcohol mixeding liquid, its volume ratio is 50:50;
Mobile phase: normal hexane and alcohol mixeding liquid, its volume ratio is 35:65;
Flow velocity: 0.5mL/min;
Column temperature: 35 DEG C;
Sample size: 10 μ L;
Detecting step:
Get and be about 25mg according to Shandong for Buddhist nun's sample, accurately weighed in the brown volumetric flask of 50mL, be diluted to scale with thinning agent ultrasonic dissolution, shake up, as need testing solution.Get need testing solution, carry out efficient liquid phase chromatographic analysis according to testing conditions, record chromatogram, the results are shown in Figure the retention time chromatographic peak of 20.92 minutes in 3, Fig. 3 is for Buddhist nun's chromatographic peak according to Shandong; The chromatographic peak of 28.29 minutes is for Buddhist nun's enantiomter impurity chromatographic peak according to Shandong.。
Embodiment 3
Testing conditions:
Instrument: Agilent high performance liquid chromatograph, AgilentDAD UV-detector;
Determined wavelength: 258nm;
Chromatographic column:
aD-H, 4.6mmX250mm, 5 μm, chiral chromatographic column;
Thinning agent: normal hexane and alcohol mixeding liquid, its volume ratio is 50:50;
Mobile phase: normal hexane and alcohol mixeding liquid, its volume ratio is 35:65;
Flow velocity: 0.5mL/min;
Column temperature: 35 DEG C;
Sample size: 10 μ L;
Detecting step:
Get according to Shandong appropriate for Buddhist nun's sample, be about equivalent to according to Shandong for Buddhist nun 25mg, put in the brown volumetric flask of 50mL, 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 the retention time chromatographic peak of 20.91 minutes in 4, Fig. 4 is for Buddhist nun's chromatographic peak according to Shandong; The chromatographic peak of 28.28 minutes is for Buddhist nun's enantiomter impurity chromatographic peak according to Shandong.
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 (2)
1. detect according to the method for Shandong for Buddhist nun, it comprises: detect on high performance liquid chromatograph, and chromatographic column is CHIRALPAK-AD-H, 250mmX4.6mm, 5 μm, chiral chromatographic column; Mobile phase is the mixed solvent of alkane solvent and alcoholic solvent, and the volume ratio of alkane solvent and alcoholic solvent is 35:65; Column temperature is 35 DEG C; Flow velocity is 0.5mL/min; Determined wavelength is 258nm, and wherein said alkane solvent is normal hexane; Described alcohol is etoh solvent.
2. method according to claim 1, also comprise and being diluted sample thinning agent to be detected, described thinning agent is the mixed solvent of normal hexane and ethanol, and in mixed solvent, the volume ratio of normal hexane and ethanol is 50:50.
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Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016164404A1 (en) * | 2015-04-06 | 2016-10-13 | Janssen Pharmaceutica Nv | Compositions containing ibrutinib |
| CN106146516B (en) * | 2015-04-20 | 2019-02-15 | 北京睿创康泰医药研究院有限公司 | The preparation method of Buddhist nun's impurity of the drug is replaced according to Shandong |
| CN106153797B (en) * | 2015-04-20 | 2017-08-29 | 北京睿创康泰医药研究院有限公司 | It is a kind of to replace Buddhist nun's preparation Related substance method according to Shandong for Buddhist nun and according to Shandong |
| CN106153798B (en) * | 2015-04-22 | 2017-08-29 | 北京睿创康泰医药研究院有限公司 | It is a kind of to be used to analyze the purposes for doing reference standard about the HPLC methods and these impurity of material for Buddhist nun's preparation according to Shandong for Buddhist nun and according to Shandong |
| CN107764907B (en) * | 2016-08-22 | 2020-07-10 | 广东东阳光药业有限公司 | Method for determining content of alogliptin enantiomer in alogliptin bulk drug |
| CN107014943B (en) * | 2017-06-07 | 2018-08-21 | 福建省微生物研究所 | A kind of detection method for replacing Buddhist nun's enantiomter according to Shandong |
| CN111007157B (en) * | 2018-10-08 | 2022-07-26 | 上海柏狮生物科技有限公司 | Purity detection method in ibrutinib preparation process |
| CN114527205A (en) * | 2022-01-21 | 2022-05-24 | 石家庄四药有限公司 | Method for detecting isomer of 2-tert-butyloxycarbonylamino-N-benzyl-3-methoxypropionamide |
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| CN103319488A (en) * | 2007-03-28 | 2013-09-25 | 环状药物公司 | Inhibitors of bruton's tyrosine kinase |
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| CN103319488A (en) * | 2007-03-28 | 2013-09-25 | 环状药物公司 | Inhibitors of bruton's tyrosine kinase |
| CN104039325A (en) * | 2011-10-19 | 2014-09-10 | 药品循环公司 | Use of inhibitors of bruton's tyrosine kinase (btk) |
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Effective date of registration: 20170727 Address after: Dam zone 512721 Guangdong city of Shaoguan province Ruyuan Yao Autonomous County town of dragon bay Hou Gong Du milk Patentee after: Ru Yuan Dongyang light pharmaceutcal corporation, Ltd Address before: 523808 Guangdong city of Dongguan province Hubei Songshan Industrial Park Industrial Road No. 1 Patentee before: Dongyangguang Pharmaceutical Co., Ltd., Guangdong |
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