CN111624263A - Determination and analysis method for IMP17 content in brexpiprazole - Google Patents
Determination and analysis method for IMP17 content in brexpiprazole Download PDFInfo
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- CN111624263A CN111624263A CN201811600051.2A CN201811600051A CN111624263A CN 111624263 A CN111624263 A CN 111624263A CN 201811600051 A CN201811600051 A CN 201811600051A CN 111624263 A CN111624263 A CN 111624263A
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Abstract
The invention discloses a method for determining and analyzing the content of IMP17 in ipiprazole, which directly uses a high performance liquid chromatography-mass spectrometer to determine the content of 7- (4-bromobutoxy) quinoline-2- (1H) -ketone (hereinafter referred to as IMP17) in ipiprazole. Compared with the prior art, the analysis method has the characteristics of good specificity, good reproducibility, extremely high sensitivity, suitability for trace analysis and the like.
Description
Technical Field
The invention relates to a method for directly measuring the content of 7- (4-bromobutoxy) quinoline-2 (1H) -ketone (IMP 17 for short) in ipiprazole by using a high performance liquid chromatography-mass spectrometer. The method can well control the content of trace IMP17 in the bulk drugs and preparations, provides guarantee for the healthy and safe medication of patients, and belongs to the technical field of medicines.
Background
Brexpiprazole, chemical name Brexpiprazole.
The compound is the first dopamine, partial 5-HT1A receptor agonist and 5-HT2A receptor antagonist compound which are developed by North Danarel and Tsukamur Japan, is considered to be another heavy pound variety after aripiprazole which is a popular drug developed by the company, has better curative effect and tolerance, and can reduce adverse reactions such as incapability of sitting still, uneasiness and/or insomnia of patients. Meanwhile, phase III clinical studies of ipiprazole treatment "agitation associated with dementia of the alzheimer type", treatment of "Post Traumatic Stress Disorder (PTSD)" as a follow-up therapy on the basis of an antidepressant, and treatment of "manic episodes associated with bipolar disorder" are also underway. The structure of the brexpiprazole is as follows:
the brexpiprazole contains reaction residual IMP17, and the structure is as follows:
accurate quantitative determination of trace amounts of IMP17 in ipiprazole is extremely challenging. It is difficult to directly measure the trace amount by gas chromatography, liquid chromatography and the like.
At present, only the method for determining the content of the constant 7- (4-bromobutoxy) quinoline-2 (1H) -ketone in the brexpiprazole adopts the classical chromatography, and has the defects of great specificity, sensitivity, method precision and repeatability, and cannot provide a reliable trace analysis result. In order to overcome the defects of the original method, the invention adopts a high performance liquid chromatography-mass spectrometer to directly measure the content of IMP17 in the brexpiprazole. The analysis method has the characteristics of simple operation, good specificity, extremely high sensitivity, good reproducibility and the like.
Disclosure of Invention
As mentioned above, there are various drawbacks to directly and accurately quantitatively determining the trace amount of IMP 17. However, by utilizing the characteristics that the IMP17 has strong stability and is very suitable for reversed-phase liquid chromatography separation, and the IMP17 is easy to ionize in a mass detector and has a stable molecular structure suitable for quantitative analysis, the IMP17 can be directly measured by adopting a high performance liquid chromatography-mass spectrometer. In addition, the sensitive absorption of IMP17 on the mass spectrometer greatly improves the sensitivity and specificity of the method.
The Epipiprazole has been found to have very good solubility in methanol by experimentation. The present invention will use methanol as a diluent.
The invention relates to a method for determining and analyzing the content of IMP17 in brexpiprazole, which is to directly determine the content of IMP17 in brexpiprazole by using a high performance liquid chromatography-mass spectrometer.
Methanol was used as a diluent in the above sample preparation.
The ion mode is selected by adopting a high performance liquid chromatography-mass spectrometer and positive ions.
The method comprises the following steps:
(1) preparing an epipiprazole raw material or preparation powder, and taking a methanol solution as a diluent to prepare a sample solution;
(2) octadecylsilane chemically bonded silica chromatographic column is adopted, and mobile phase is 0.05% -0.2% formic acid or acetic acid or trifluoroacetic acid or perfluorobutyric acid water solution and acetonitrile for gradient elution.
(3) Setting the flow rate of the mobile phase to be 0.3-1.2mL/min, and controlling the column temperature to be 25-45 ℃.
(4) And (3) taking 2 mu L of the sample solution obtained in the step (1), injecting a sample, and recording a mass spectrum total ion flow diagram.
(5) And (3) selecting positive ions in an ion mode by adopting a mass spectrum detector, sampling the sample solution in the step (1), and recording an IMP17 mass spectrum ion flow diagram.
The technical scheme adopted by the invention is as follows:
sample pretreatment:
diluting liquid: chromatographic grade methanol was used.
IMP17 standard solution: a187.5 ng/mL solution of IMP17 was prepared with the diluent.
Sample solution: precisely weighing 25mg of sample in a 50mL volumetric flask, dissolving with diluent, fixing the volume to a scale, and injecting.
The chromatographic column used in the invention is as follows: octadecylsilane chemically bonded silica chromatographic column. The flow rate is 0.3-1.2 mL/min. The column temperature is 25-45 ℃. Mobile phase A: 0.05% -0.2% aqueous formic acid or acetic acid or trifluoroacetic acid or perfluorobutyric acid, mobile phase B: acetonitrile, gradient as follows:
| A | B | |
| 0min | 90％ | 10％ |
| 8min | 10％ | 90％ |
a mass spectrum detector: positive ion mode, [ M + H ]]+:296
Description of the drawings:
FIG. 1: an IMP17 mass spectrometry bar graph obtained according to example 1 of the present invention;
FIG. 2 is a drawing: the mass spectrum total ion flow chart of the IMP17 standard product obtained according to the embodiment 1 of the invention;
FIG. 3: according to the general ion flow diagram of the mass spectrum of the brexpiprazole sample obtained in the embodiment 2 of the invention;
FIG. 4 is a drawing: according to the total ion flow chart of the sample adding and recovery mass spectrum of the brexpiprazole sample obtained in the embodiment 3 of the invention.
Detailed Description
For better understanding of the technical solutions of the present invention, the following embodiments are further described, but not limited to, the present invention.
Example one
Instruments and conditions:
high performance liquid chromatography mass spectrometer: agilent 1260 definition, MS Detector.
A chromatographic column: octadecylsilane chemically bonded silica chromatographic column
Mobile phase: a: 0.05% -0.2% aqueous formic acid or acetic acid or trifluoroacetic acid or perfluorobutyric acid solution B: and (3) acetonitrile.
The gradient is as follows: the organic phase ratio is changed from 10% to 90% in 0-8.0 min.
Column temperature: at 45 ℃.
Flow rate: 1.0mL/min
Selecting positive ions: 296
Sample introduction volume: 2 μ L
The experimental steps are as follows:
1) preparing a mobile phase A: precisely measuring 1.0mL of formic acid, dissolving in 1000mL of water, and uniformly mixing.
2) And (3) diluting liquid B: methanol
3) Standard solution C: precisely weighing about 19mg IMP17 in a 50mL volumetric flask, adding B for dissolving to a constant volume, shaking up, precisely weighing 0.5mL, placing in another 10mL volumetric flask, adding B for constant volume, shaking up, precisely weighing 1.0mL, placing in another 100mL volumetric flask, shaking up to obtain a standard solution C, injecting, and recording a mass spectrum bar chart, which is shown in a typical chart 1. The IMP17 mass spectrum total ion flow graph is recorded, see typical figure 2.
Example two
Instruments and conditions:
high performance liquid chromatograph: agilent 1260 definition, MS Detector.
A chromatographic column: octadecylsilane chemically bonded silica chromatographic column
Mobile phase: a: 0.05% -0.2% aqueous formic acid or acetic acid or trifluoroacetic acid or perfluorobutyric acid solution B: and (3) acetonitrile.
The gradient is as follows: the organic phase ratio is changed from 10% to 90% in 0-8.0 min.
Column temperature: at 45 ℃.
Flow rate: 1.0mL/min
Selecting positive ions: 296
Sample introduction volume: 2 μ L
The experimental steps are as follows:
1) preparing a mobile phase A: precisely measuring 1.0mL of formic acid, dissolving in 1000mL of water, and uniformly mixing.
2) And (3) diluting liquid B: methanol
3) Standard solution C: precisely weighing about 19mg IMP17 in a 100mL volumetric flask, adding B to dissolve to a constant volume, shaking up, precisely weighing 0.5mL, placing in another 10mL volumetric flask, adding B to a constant volume, shaking up, precisely weighing 1.0mL, placing in another 100mL volumetric flask, and shaking up to obtain the standard solution C.
4) And D, precisely weighing about 25mg of the brexpiprazole sample, putting the brexpiprazole sample into a 50mL volumetric flask, adding B to fix the volume to obtain a sample solution D, and injecting. The IMP17 mass spectrum total ion flow graph is recorded, see typically figure 3.
EXAMPLE III
Instruments and conditions:
high performance liquid chromatograph: agilent 1260 definition, MS Detector.
A chromatographic column: octadecylsilane chemically bonded silica chromatographic column
Mobile phase: a: 0.05% -0.2% aqueous formic acid or acetic acid or trifluoroacetic acid or perfluorobutyric acid solution B: and (3) acetonitrile.
The gradient is as follows: the organic phase ratio is changed from 10% to 90% in 0-8.0 min.
Column temperature: at 45 ℃.
Flow rate: 1.0mL/min
Selecting positive ions: 296
Sample introduction volume: 2 μ L
The experimental steps are as follows:
1) preparing a mobile phase A: precisely measuring 1.0mL of formic acid, dissolving in 1000mL of water, and uniformly mixing.
2) And (3) diluting liquid B: methanol
3) Standard solution C: precisely weighing about 19mg IMP17 in a 100mL volumetric flask, adding B to dissolve to a constant volume, shaking up, precisely weighing 0.5mL, placing in another 10mL volumetric flask, adding B to a constant volume, shaking up, precisely weighing 1.0mL, placing in another 100mL volumetric flask, and shaking up to obtain the standard solution C.
4) And E, precisely weighing about 25mg of the brexpiprazole sample, placing the brexpiprazole sample in a 50mL volumetric flask, dissolving the brexpiprazole sample by using the standard solution C, titrating the solution to a scale, uniformly mixing the solution and injecting the sample. The IMP17 mass spectrum total ion flow graph is recorded, see typical figure 4.
Claims (3)
1. A method for determining and analyzing the content of suspected genotoxic impurity 7- (4-bromobutoxy) quinoline-2 (1H) -ketone (IMP 17) in ipiprazole is characterized in that the content of trace IMP17 in ipiprazole is directly determined by a high performance liquid chromatography-mass spectrometer.
2. The method of claim 1, wherein the positive ion is selected for ion mode using a high performance liquid chromatography-mass spectrometer.
3. The method according to claim 1, characterized in that the method comprises the following steps:
(1) preparing an epipiprazole raw material or preparation powder, and taking a methanol solution as a diluent to prepare a sample solution;
(2) performing gradient elution by using an octadecylsilane chemically bonded silica chromatographic column and a mobile phase of 0.05-0.2% formic acid, acetic acid, trifluoroacetic acid or perfluorobutyric acid aqueous solution and acetonitrile;
(3) setting the flow rate of the mobile phase to be 0.3-1.2mL/min, and controlling the column temperature to be 25-45 ℃;
(4) taking 2 mu L of the sample solution in the step (1), carrying out sample introduction, and recording a mass spectrum total ion flow diagram;
(5) and (3) selecting positive ions in an ion mode by adopting a mass spectrum detector, sampling the sample solution in the step (1), and recording a mass spectrum ion flow diagram.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008026220A1 (en) * | 2006-08-28 | 2008-03-06 | Lupin Limited | A process for purification of 7-(4-bromobutoxy)-3,4 dihydrocarbostyril, an intermediate for manufacture of aripirazole |
| CN103923002A (en) * | 2013-01-16 | 2014-07-16 | 广东东阳光药业有限公司 | Preparation method of aripiprazole intermediate |
| CN111393423A (en) * | 2019-01-03 | 2020-07-10 | 上海科胜药物研发有限公司 | Epipiprazole impurity compound and preparation method thereof |
-
2019
- 2019-02-27 CN CN201811600051.2A patent/CN111624263A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008026220A1 (en) * | 2006-08-28 | 2008-03-06 | Lupin Limited | A process for purification of 7-(4-bromobutoxy)-3,4 dihydrocarbostyril, an intermediate for manufacture of aripirazole |
| CN103923002A (en) * | 2013-01-16 | 2014-07-16 | 广东东阳光药业有限公司 | Preparation method of aripiprazole intermediate |
| CN111393423A (en) * | 2019-01-03 | 2020-07-10 | 上海科胜药物研发有限公司 | Epipiprazole impurity compound and preparation method thereof |
Non-Patent Citations (4)
| Title |
|---|
| A SRAVANTH KUMAR等: "Delineating an alternate convergent synthesis of brexpiprazole: a novel use of commercial 6,7-dihydrobenzo[b]thiophen-4(5H)-one as precursor to an efficacious Buchwald–Hartwig amination step", 《J. CHEM. SCI.》 * |
| GOSULA VENKAT RAMI REDDY等: "Identification of degradation products in Aripiprazole tablets by LC‐QToF mass spectrometry", 《EUROPEAN JOURNAL OF CHEMISTRY》 * |
| T. POORNA CHANDER等: "Synthesis and Characterization of Related Compounds of Aripiprazole, an Antipsychotic Drug Substance", 《SYNTHETIC COMMUNICATIONS》 * |
| 王先恒等: "阿立哌唑原料药中二聚体的分离制备和结构鉴定", 《化学研究与应用》 * |
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