CN109975435A - The measuring method of isopropyl mesylate content in a kind of safinamide - Google Patents
The measuring method of isopropyl mesylate content in a kind of safinamide Download PDFInfo
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- CN109975435A CN109975435A CN201711441911.8A CN201711441911A CN109975435A CN 109975435 A CN109975435 A CN 109975435A CN 201711441911 A CN201711441911 A CN 201711441911A CN 109975435 A CN109975435 A CN 109975435A
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- Prior art keywords
- safinamide
- solution
- acetonitrile
- sample
- isopropyl mesylate
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- SWWHCQCMVCPLEQ-UHFFFAOYSA-N propan-2-yl methanesulfonate Chemical compound CC(C)OS(C)(=O)=O SWWHCQCMVCPLEQ-UHFFFAOYSA-N 0.000 title claims abstract description 26
- NEMGRZFTLSKBAP-LBPRGKRZSA-N safinamide Chemical compound C1=CC(CN[C@@H](C)C(N)=O)=CC=C1OCC1=CC=CC(F)=C1 NEMGRZFTLSKBAP-LBPRGKRZSA-N 0.000 title claims abstract description 24
- 229950002652 safinamide Drugs 0.000 title claims abstract description 23
- 238000000034 method Methods 0.000 title claims abstract description 11
- 238000001212 derivatisation Methods 0.000 claims abstract description 7
- 238000000589 high-performance liquid chromatography-mass spectrometry Methods 0.000 claims abstract description 6
- 238000005259 measurement Methods 0.000 claims abstract description 6
- 238000004458 analytical method Methods 0.000 claims abstract description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 45
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 18
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 16
- 239000000523 sample Substances 0.000 claims description 16
- 150000002500 ions Chemical class 0.000 claims description 15
- 239000007788 liquid Substances 0.000 claims description 14
- 239000000243 solution Substances 0.000 claims description 14
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 238000001819 mass spectrum Methods 0.000 claims description 11
- 239000012488 sample solution Substances 0.000 claims description 10
- 238000010790 dilution Methods 0.000 claims description 9
- 239000012895 dilution Substances 0.000 claims description 9
- 150000001768 cations Chemical class 0.000 claims description 7
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 6
- 235000019253 formic acid Nutrition 0.000 claims description 6
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 claims description 6
- YPJUNDFVDDCYIH-UHFFFAOYSA-N perfluorobutyric acid Chemical compound OC(=O)C(F)(F)C(F)(F)C(F)(F)F YPJUNDFVDDCYIH-UHFFFAOYSA-N 0.000 claims description 6
- -1 2- mercaptopyridine acetonitrile Chemical compound 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 238000010828 elution Methods 0.000 claims description 2
- 238000009472 formulation Methods 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims description 2
- 230000003595 spectral effect Effects 0.000 claims description 2
- 239000003153 chemical reaction reagent Substances 0.000 claims 1
- 231100000025 genetic toxicology Toxicity 0.000 claims 1
- 230000001738 genotoxic effect Effects 0.000 claims 1
- 239000012535 impurity Substances 0.000 claims 1
- 230000002349 favourable effect Effects 0.000 abstract description 2
- 230000035945 sensitivity Effects 0.000 abstract description 2
- 238000004454 trace mineral analysis Methods 0.000 abstract 1
- 239000012071 phase Substances 0.000 description 11
- 239000012086 standard solution Substances 0.000 description 8
- 238000002474 experimental method Methods 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 102000010909 Monoamine Oxidase Human genes 0.000 description 3
- 108010062431 Monoamine oxidase Proteins 0.000 description 3
- 238000004445 quantitative analysis Methods 0.000 description 3
- 238000005070 sampling Methods 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 241000206601 Carnobacterium mobile Species 0.000 description 1
- QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical class CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 229940035678 anti-parkinson drug Drugs 0.000 description 1
- 239000000939 antiparkinson agent Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 230000004112 neuroprotection Effects 0.000 description 1
- 238000002203 pretreatment Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
- 238000011125 single therapy Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
Classifications
-
- 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
-
- 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
- G01N30/89—Inverse chromatography
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- Physics & Mathematics (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- 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 a kind of measuring methods of isopropyl mesylate content in safinamide, and this method is using chemical derivatization and the content of combination high performance liquid chromatography-mass spectrometry instrument measurement safinamide isopropyl mesylate.The analysis method has specificity good compared with prior art, and favorable reproducibility, sensitivity is high, is suitble to the features such as doing trace analysis.
Description
Technical field
The present invention relates to determine first in safinamide using chemical derivatization and in conjunction with high performance liquid chromatography-mass spectrometry instrument
The content of sulfonic acid isopropyl ester.The method can preferably control trace isopropyl mesylate content in bulk pharmaceutical chemicals and preparation, be patient
Healthy and safe medication provide safeguard, belong to pharmaceutical technology field.
Technical background
Safinamide, chemical name Safinamide mesilate.
Safinamide is a kind of selective monoamine oxidase B (MAO-B) inhibitor, in addition to it can inhibit MAO-B, also
With the additional function for inhibiting glutamic neuron (glutamaterelease), theoretically, this may generate neuroprotection work
With.Usually as single therapy early stage PD patient, or it is added in the therapeutic scheme of advanced stage PD patient can preferably control
Symptom processed and the dosage for reducing other required anti-parkinson drugs.Safinamide structure is as follows:
Containing remaining isopropyl mesylate is reacted in safinamide, structure is as follows:
The isopropyl mesylate content for measuring to accurate quantitative analysis trace in safinamide is extremely challenging.It is difficult to adopt gas
Phase, liquid chromatogram etc. carry out trace to it and directly measure.
Currently, not finding the analysis method in relation to trace isopropyl mesylate content in measurement safinamide.So this
Invention is using chemical derivatization and isopropyl mesylate in high performance liquid chromatography-mass spectrometry instrument measurement safinamide is combined to contain
Amount.The analysis method has the characteristics that easy to operate, specificity is good, sensitive high, favorable reproducibility.It is as follows that it derives principle:
Summary of the invention
As described above, directly there are various defects for accurate quantitative analysis measurement trace isopropyl mesylate.However, utilizing methanesulfonic acid
Isopropyl ester has stability not strong and is very suitable to derivatization reaction and the feature that separates of utilization reversed-phase liquid chromatography, and in mass spectrum
It is easy to ionize in detector and has the characteristics that the molecular structure of stable suitable quantitative analysis, efficient liquid phase can be used
Chromatograph-mas spectrometer directly measures.In addition to this, isopropyl mesylate derivative has in mass detector sensitively absorbs this
One feature greatly improves the sensitivity of this method and specificity.
It is found by experiment that safinamide in acetonitrile: having extraordinary dissolubility, therefore this in water=50:50 (%V/V)
Invention will use acetonitrile: water=50:50 (%V/V) is as diluent.
The present invention relates to a kind of measuring method of isopropyl mesylate content in safinamide, this method be chemical derivatization simultaneously
In conjunction with the content of isopropyl mesylate in high performance liquid chromatography-mass spectrometry instrument measurement safinamide.
Use acetonitrile in above-mentioned sample preparation: water=50:50 (%V/V) is as dilution.
It is above-mentioned to use high performance liquid chromatography-mass spectrometry instrument, cation choice ion pattern.
This method including the following steps:
(1) safinamide bulk pharmaceutical chemicals or powder formulation are taken, using acetonitrile: water=50:50 (%V/V) solution is as dilution system
It is standby to obtain sample solution；
(2) octadecyl silane chromatographic column is used, mobile phase is 0.05%-0.2% formic acid or acetic acid or trifluoro second
Acid or perfluorobutyric acid aqueous solution and acetonitrile, carry out gradient elution.
(3) setting flow rate of mobile phase is 0.3-1.2mL/min, and column temperature controls between 25 DEG C -45 DEG C.
(4) the 5 μ L of sample solution of step (1) is taken, sample introduction records mass spectrum total ion current figure.
(5) mass detector is used, ion mode selects cation, takes the sample solution sample introduction of (1), and record methanesulfonic acid is different
Propyl ester derivative mass spectral ion current figure.
(6) using 2- mercaptopyridine acetonitrile solution as derivative liquid.
The technical solution adopted by the invention is as follows:
Sample pre-treatments:
Dilution: acetonitrile: water=50:50 (%V/V).
Derivative liquid: 2- mercaptopyridine acetonitrile solution.
Isopropyl mesylate derivative standard solution: the isopropyl mesylate for preparing 150ng/mL with dilution precision is molten
Liquid.Isometric solution and derivative liquid mixing is taken to carry out after deriving, sample introduction.
Sample solution: precision weighs 100mg sample in the volumetric flask of 10mL, and scale is dissolved and be settled to dilution,
Isometric solution and derivative liquid mixing is taken to carry out after deriving, sample introduction.
The present invention uses chromatographic column are as follows: octadecyl silane chromatographic column.Flow velocity 0.3-1.2mL/min.25 DEG C of column temperature-
45℃.Mobile phase A: 0.05%-0.2% formic acid or acetic acid or trifluoroacetic acid or perfluorobutyric acid aqueous solution, Mobile phase B: acetonitrile, ladder
Spend as follows: 0min~8.0min, organic Phase Proportion become 90% from 10%.Mass detector: positive ion mode, [M+H]+: 154
Detailed description of the invention:
Attached drawing 1: according to embodiments of the present invention 1 obtained isopropyl mesylate derivative mass spectrum rod figure；
Attached drawing 2: according to embodiments of the present invention 1 obtained isopropyl mesylate standard items derivative mass spectrum total ion current figure；
Attached drawing 3: according to embodiments of the present invention 2 obtained safinamide sample mass spectrum total ion current figures；
Attached drawing 4: according to embodiments of the present invention 3 obtained safinamide sample pipetting volume rate of recovery mass spectrum total ion current figures.
Specific embodiment
For a better understanding of the technical solution of the present invention, making furtherly below with reference to specific embodiments of the present invention
It is bright, but it is not limited to the present invention.
Embodiment one
Instrument and condition:
High performance liquid chromatography mass spectrometer: Agilent 1260infinity, MS detector.
Chromatographic column: octadecyl silane chromatographic column
Mobile phase: A:0.05%-0.2% formic acid or acetic acid or trifluoroacetic acid or perfluorobutyric acid aqueous solution
B: acetonitrile.
Gradient is as follows: 0~8.0min, and organic Phase Proportion becomes 90% from 10%.
Column temperature: 35 DEG C.
Flow velocity: 1.0mL/min
Selection cation: 154
Sampling volume: 5 μ L
Experimental procedure:
1) mobile phase A is prepared: precision measures 1.0mL trifluoroacetic acid and is dissolved in 1000mL water, mixes.
2) dilution B: acetonitrile: water=50:50 (%V/V)
3) standard solution C: precision weighs about 300mg isopropyl mesylate in 100mL volumetric flask, adds B to dissolve constant volume, shakes
Even, precision measures 1.0mL and is placed in another 100mL volumetric flask, adds B constant volume, shakes up, and precision measures 1.0mL and is placed in another 100mL
In volumetric flask, add B constant volume, isometric solution and derivative liquid mixing is taken to carry out after deriving to get standard solution C, sample introduction, note
Mass spectrum rod figure is recorded, sees attached drawing 1.Isopropyl mesylate derivative mass spectrum total ion current figure is recorded, sees attached drawing 2.
Embodiment two
Instrument and condition:
High performance liquid chromatograph: Agilent 1260infinity, MS detector.
Chromatographic column: octadecyl silane chromatographic column
Mobile phase: A:0.05%-0.2% formic acid or acetic acid or trifluoroacetic acid or perfluorobutyric acid aqueous solution
B: acetonitrile.
Gradient is as follows: 0~8.0min, and organic Phase Proportion becomes 90% from 10%.
Column temperature: 35 DEG C.
Flow velocity: 1.0mL/min
Selection cation: 154
Sampling volume: 5 μ L
Experimental procedure:
1) mobile phase A is prepared: precision measures 1.0mL trifluoroacetic acid and is dissolved in 1000mL water, mixes.
2) dilution B: acetonitrile: water=50:50 (%V/V)
3) standard solution C: precision weighs about 300mg isopropyl mesylate in 100mL volumetric flask, adds B to dissolve constant volume, shakes
Even, precision measures 1.0mL and is placed in another 100mL volumetric flask, adds B constant volume, shakes up, and precision measures 1.0mL and is placed in another 100mL
In volumetric flask, add B constant volume, isometric solution and derivative liquid mixing is taken to carry out after deriving to get standard solution C.
4) sample solution D: precision weighs about 200mg safinamide sample and is placed in 10mL volumetric flask, adds B constant volume, takes
The solution of volume and derivative liquid mixing carry out after deriving to get sample solution D, sample introduction.Record isopropyl mesylate derivative
Mass spectrum total ion current figure is shown in attached drawing 3.
Embodiment three
Instrument and condition:
High performance liquid chromatograph: Agilent 1260infinity, MS detector.
Chromatographic column: octadecyl silane chromatographic column
Mobile phase: A:0.05%-0.2% formic acid or acetic acid or trifluoroacetic acid or perfluorobutyric acid aqueous solution
B: acetonitrile.
Gradient is as follows: 0~8.0min, and organic Phase Proportion becomes 90% from 10%.
Column temperature: 35 DEG C.
Flow velocity: 1.0mL/min
Selection cation: 154
Sampling volume: 5 μ L
Experimental procedure:
1) mobile phase A is prepared: precision measures 1.0mL trifluoroacetic acid and is dissolved in 1000mL water, mixes.
2) dilution B: acetonitrile: water=50:50 (%V/V)
3) standard solution C: precision weighs about 300mg isopropyl mesylate in 100mL volumetric flask, adds B to dissolve constant volume, shakes
Even, precision measures 1.0mL and is placed in another 100mL volumetric flask, adds B constant volume, shakes up, and precision measures 1.0mL and is placed in another 100mL
In volumetric flask, add B constant volume, isometric solution and derivative liquid mixing is taken to carry out after deriving to get standard solution C.
4) sample solution D: precision weighs about 200.0mg safinamide sample, is placed in 10mL volumetric flask, uses standard solution
C dissolves and is settled to scale, mixes, and takes isometric solution and derivative liquid mixing to carry out after deriving, sample introduction.Record methanesulfonic acid
Isopropyl ester derivative mass spectrum total ion current figure, is shown in attached drawing 4.
Claims (3)
1. the measuring method of genotoxicity impurity isopropyl mesylate content in a kind of safinamide, it is characterised in that using chemistry
Derive and combine the content of the isopropyl mesylate of trace in high performance liquid chromatography-mass spectrometry instrument measurement safinamide.
2. analysis method according to claim 1, it is characterised in that using chemical derivatization and combine high performance liquid chromatography-matter
Combined instrument is composed, ion mode selects cation.
3. according to claim 1, it is characterised in that this method including the following steps:
(1) safinamide bulk pharmaceutical chemicals or powder formulation are taken, using acetonitrile: water=50:50 (%V/V) solution is prepared into as dilution
To sample solution；
(2) use octadecyl silane chromatographic column, mobile phase be 0.05%-0.2% formic acid or acetic acid or trifluoroacetic acid or
Perfluorobutyric acid aqueous solution and acetonitrile carry out gradient elution；
(3) setting flow rate of mobile phase is 0.3-1.2mL/min, and column temperature controls between 25 DEG C -45 DEG C；
(4) the 5 μ L of sample solution of step (1) is taken, sample introduction records mass spectrum total ion current figure；
(5) mass detector is used, ion mode selects cation, takes the sample solution sample introduction of (1), records mass spectral ion current
Figure；
(6) using 2- mercaptopyridine acetonitrile solution as derivatization reagent.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711441911.8A CN109975435A (en) | 2017-12-27 | 2017-12-27 | The measuring method of isopropyl mesylate content in a kind of safinamide |
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|---|---|---|---|
| CN201711441911.8A CN109975435A (en) | 2017-12-27 | 2017-12-27 | The measuring method of isopropyl mesylate content in a kind of safinamide |
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| CN109975435A true CN109975435A (en) | 2019-07-05 |
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| CN201711441911.8A Pending CN109975435A (en) | 2017-12-27 | 2017-12-27 | The measuring method of isopropyl mesylate content in a kind of safinamide |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110618219A (en) * | 2019-09-25 | 2019-12-27 | 深圳海王医药科技研究院有限公司 | Method for detecting residual solvent of trifluoromethanesulfonic acid |
| CN113390986A (en) * | 2021-05-31 | 2021-09-14 | 河北国龙制药有限公司 | Method for detecting genotoxic impurities in salfinamide mesylate |
| CN116124926A (en) * | 2022-12-20 | 2023-05-16 | 华道(上海)生物医药有限公司 | Method for determining content of 2-mercaptopyridine in plasmid |
-
2017
- 2017-12-27 CN CN201711441911.8A patent/CN109975435A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110618219A (en) * | 2019-09-25 | 2019-12-27 | 深圳海王医药科技研究院有限公司 | Method for detecting residual solvent of trifluoromethanesulfonic acid |
| CN110618219B (en) * | 2019-09-25 | 2022-08-19 | 深圳海王医药科技研究院有限公司 | Method for detecting residual solvent of trifluoromethanesulfonic acid |
| CN113390986A (en) * | 2021-05-31 | 2021-09-14 | 河北国龙制药有限公司 | Method for detecting genotoxic impurities in salfinamide mesylate |
| CN113390986B (en) * | 2021-05-31 | 2022-04-08 | 河北国龙制药有限公司 | Method for detecting genotoxic impurities in salfinamide mesylate |
| CN116124926A (en) * | 2022-12-20 | 2023-05-16 | 华道(上海)生物医药有限公司 | Method for determining content of 2-mercaptopyridine in plasmid |
| CN116124926B (en) * | 2022-12-20 | 2024-05-03 | 华道(上海)生物医药有限公司 | Method for determining content of 2-mercaptopyridine in plasmid |
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