CN115326942B - Analysis method for measuring thiophene tosylate - Google Patents

Analysis method for measuring thiophene tosylate Download PDF

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CN115326942B
CN115326942B CN202210161316.3A CN202210161316A CN115326942B CN 115326942 B CN115326942 B CN 115326942B CN 202210161316 A CN202210161316 A CN 202210161316A CN 115326942 B CN115326942 B CN 115326942B
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mobile phase
thiophene
tosylate
mass spectrum
gradient elution
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CN115326942A (en
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苗德权
邓瑜
李安排
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Suzhou Zhengji Pharmaceutical Research Co ltd
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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
    • 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
    • G01N30/04—Preparation or injection of sample to be analysed
    • G01N30/06—Preparation
    • 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
    • G01N30/62—Detectors specially adapted therefor
    • G01N30/72—Mass spectrometers
    • 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
    • G01N30/86—Signal analysis
    • G01N30/8675—Evaluation, i.e. decoding of the signal into analytical information
    • 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
    • G01N2030/022—Column chromatography characterised by the kind of separation mechanism
    • G01N2030/027—Liquid 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
    • G01N30/02—Column chromatography
    • G01N30/04—Preparation or injection of sample to be analysed
    • G01N30/06—Preparation
    • G01N2030/062—Preparation extracting sample from raw material
    • 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

Abstract

The invention provides an analysis method for measuring thiophene tosylate, which adopts a liquid chromatography mass spectrometer to detect and analyze the thiophene tosylate, adopts a chromatographic column with octadecylsilane chemically bonded silica as a filler, adopts an acid aqueous solution as a mobile phase A and adopts lower alkyl alcohol or acetonitrile as a mobile phase B, wherein the volume concentration of the mobile phase A is 0.1-0.5%, and the volume fraction of the mobile phase B is 25-50%; gradient elution was performed. The invention provides an accurate, efficient and highly specific detection and analysis method for the ppm-level determination of the thiophene tosylate.

Description

Analysis method for measuring thiophene tosylate
Technical Field
The invention relates to the technical field of drug detection and analysis, in particular to an analysis method for measuring thiophene tosylate.
Background
Clopidogrel bisulfate has the chemical name: s (+) -2- (2-chlorophenyl) -2- (4, 5,6, 7-tetrahydrothiophene [3,2-c ]]And pyridine-5) methyl acetate bisulfate, which was developed by Sanofi corporation in France in 1986, is a novel highly potent antiplatelet aggregation drug. The CAS number is: 120202-66-6, molecular formula C 16 H 16 ClNO 2 ·H 2 SO 4 The molecular weight is: 419.90, the structural formula is as follows:
。
clopidogrel hydrogen sulfateThe main synthesis reaction process is as follows: in a mixed system of water and toluene, the pH value of the o-chlorobenzeneglycine methyl ester tartrate is regulated by a sodium carbonate solution to obtain a solution of methyl ester toluene (+/-chiral structure), and the solution reacts with dipotassium hydrogen phosphate and an intermediate thiophene p-toluenesulfonate under the catalysis of tetrabutylammonium bromide, and then a hydrogen chloride methanol solution is used for salifying to obtain a condensate. Wherein the molecular formula of the intermediate thiophene tosylate is C 13 H 14 O 3 S 2 The molecular weight is: 282.40, the structural formula is as follows:
。
at present, although the quality control of the impurity content of clopidogrel bisulfate has pharmacopoeia records, no published LCMS detection method exists on the quality control of the impurity (thiophene tosylate), the thiophene tosylate is taken as a key intermediate, the method has a p-toluenesulfonate genotoxicity warning structure, only two steps and three steps of reaction steps are needed from the finished clopidogrel bisulfate, and an analysis method capable of effectively detecting the ppm level of the thiophene tosylate in the clopidogrel bisulfate is established for effectively controlling the impurity.
Disclosure of Invention
The invention aims to:
because the p-toluenesulfonic acid thiophene ester has a p-toluenesulfonic acid ester genotoxicity warning structure, in order to effectively control the p-toluenesulfonic acid thiophene ester impurity in clopidogrel bisulfate and examine the transmission of the impurity, the invention provides an analysis method capable of effectively measuring the ppm level of the p-toluenesulfonic acid thiophene ester.
The invention provides the following technical scheme:
an analysis method for determining thiophene tosylate, which adopts a liquid chromatography mass spectrometer to detect and analyze the thiophene tosylate, adopts a chromatographic column with octadecylsilane chemically bonded silica as a filler, takes aqueous solution of acid as a mobile phase A, takes lower alkyl alcohol or acetonitrile as a mobile phase B, the volume concentration of the mobile phase A is 0.1-0.5%, and the starting of the mobile phase BThe volume fraction is 25% -50%; gradient elution is carried out, and the structural formula of the thiophene tosylate is as follows:。
in some preferred embodiments, the volume concentration of mobile phase a is 0.1% to 0.3%; the initial volume fraction of the mobile phase B is 40-50%.
In some more preferred embodiments, the volume concentration of mobile phase a is 0.1%; the starting volume fraction of mobile phase B was 45%.
In some embodiments, the detector is a mass spectrum detector, and the scanning mode in the mass spectrum detector is a multi-reaction detection scanning mode.
In some embodiments, the mass spectrometer detector instrument parameters are set to:
parameter name Parameter conditions
Ion source ESI source
Electron multiplication voltage 0～200V
Drying gas temperature 250～300℃
Drying air flow rate 8～12L/min
Atomization air pressure 35～45psi
Nozzle voltage 1400～1600V
Sheath air temperature 250～300℃
Sheath air flow rate 5～8L/min
Capillary voltage 3500～4500V
In some preferred embodiments, the mass spectrometer detector instrument parameters are set to:
parameter name Parameter conditions
Ion source Jet-ESI source
Electron multiplication voltage 0V
Drying gas temperature 250℃
Drying air flow rate 11L/min
Atomization air pressure 40psi
Nozzle voltage 1500V
Sheath air temperature 250℃
Sheath air flow rate 8L/min
Capillary voltage 4000V
In some embodiments, the ion detection parameters in the liquid chromatography mass spectrometer are set as:
thiophene tosylate Parent ion Ion
Quantification of 305m/z 111m/z
Qualitative nature 305m/z 195m/z
In some embodiments, the aqueous acid solution is an aqueous formic acid solution or an aqueous acetic acid solution. In some preferred embodiments, the aqueous acid solution is an aqueous formic acid solution.
In some embodiments, the lower alkyl alcohol is one or more of methanol, ethanol, isopropanol, propanol, or butanol. In some preferred embodiments, the lower alkyl alcohol is methanol.
In some embodiments, the column temperature is from 30 ℃ to 50 ℃. In some preferred embodiments, the column temperature is 40 ℃.
In some embodiments, the detection wavelength is 200nm to 220nm. In some preferred embodiments, the detection wavelength is 220nm.
In some embodiments, the sample loading is 5. Mu.l to 10. Mu.l, the mobile phase flow rate is 0.5ml/min to 0.9ml/min, and the sample tray temperature is controlled to be 2 ℃ to 8 ℃. In some preferred embodiments, the sample loading is 10. Mu.l, the mobile phase flow rate is 0.7ml/min, and the sample tray temperature is 4 ℃.
In some embodiments, the gradient elution procedure is:
in some preferred embodiments, the gradient elution procedure is:
elution time (min) Mobile phase a (%) Mobile phase B (%)
0 60～50 40～50
7 20～30 80～70
15 20～30 80～70
16 60～50 40～50
20 60～50 40～50
In some more preferred embodiments, the gradient elution procedure is:
elution time (min) Phase A (%) Phase B (%)
0 55 45
7 25 75
15 25 75
16 55 45
20 55 45
In some embodiments, the chromatographic column is Agilent ZORBAX plus C18 (4.6X100 mm,3.5 μm).
In some embodiments, the chromatography column: the particle size of the filler is 2.0-6.0 mu m, the length of the chromatographic column is 100-250 mm, and the inner diameter of the chromatographic column is 4.0-5.0 mm. In some preferred embodiments, the filler has a particle size of 3.5 μm, a column length of 100mm, and an inner diameter of 4.6mm.
The beneficial effects are that:
the invention provides an analysis method for measuring thiophene tosylate, which shows the detection advantage of thiophene tosylate at ppm level, and has extremely high specificity by detecting parent ions, quantitative ions and qualitative ions through a liquid chromatograph-mass spectrometer. The invention provides an accurate, efficient and highly specific detection method for the ppm-level determination of the thiophene tosylate.
Drawings
FIG. 1 shows the parent and quantitative and qualitative ion selection criteria of the present invention;
FIG. 2 is a schematic diagram of the detection result of example 1 of the present invention, wherein RT=11.56 min is the peak of the thiophene tosylate quantitative ion 111 m/z;
FIG. 3 is a schematic diagram of the detection result of example 1 of the present invention, wherein RT=11.56 min is the signal-to-noise ratio response value of thiophene tosylate quantitative ion 111m/z at a mass concentration of 50 ng/ml;
fig. 4 is a schematic diagram of the detection result of example 1 of the present invention, wherein rt=11.56 min is a peak of 195m/z of thiophene tosylate qualitative ion.
Detailed Description
The following describes the technical scheme in the embodiment of the present invention in detail, but the present invention is not limited to the described embodiment. Unless otherwise indicated, reagents, materials, and equipment used in the following examples were obtained by conventional conditions and methods, or by conventional commercial means.
Example 1
Instrument: agilent 1260-6460 liquid chromatograph mass spectrometer
Chromatographic column: agilent ZORBAX plus C18 (4.6X100 mm,3.5 μm)
Mobile phase: phase A: 0.1% formic acid aqueous solution
And B phase: methanol
Detection wavelength: 220nm
Flow rate: 0.7ml/min
Column temperature: 40 DEG C
Sample injection amount: 10 μl of
Sample tray temperature control: 4 DEG C
Elution procedure:
table 1: EXAMPLE 1 gradient elution procedure
Elution time (min) Phase A (%) Phase B (%)
0min 55 45
7min 25 75
15min 25 75
16min 55 45
20min 55 45
By adopting the elution procedure in the table 1, not only the separation of the thiophene tosylate impurity and the main component can be ensured, but also the occurrence of pollution caused by the fact that the excessive concentration enters the liquid chromatograph-mass spectrometer can be avoided.
When the ratio of mobile phase, column temperature, detection wavelength and flow rate in chromatographic conditions are changed slightly, for example, the initial volume fraction of mobile phase B is 40% -50%, even 25% -50%; the column temperature is 35-45 ℃ and even 30-50 ℃; the detection wavelength is 200nm-220nm; the flow rate is 0.5ml/min-0.9ml/min, even 0.5ml/min-1.5ml/min, and the detection result is not affected.
Ion source: jet-ESI
Ion detection parameters were set as follows in table 2:
table 2: ion detection parameter setting
Drying gas temperature (. Degree. C.) 250
Drying air flow rate (L/min) 11
Atomization air pressure (psi) 40
Sheath air temperature (. Degree. C.) 250
Sheath air flow rate (L/min) 8
Capillary voltage (V) ±4000
Nozzle voltage (V) ±1500
Scanning mode: multiple reaction detection scan (Multi Reaction Monitoring: MRM for short)
Mass spectrum acquisition time: 3min to 10.1min
Electron multiplication voltage (+): 0V
As shown in FIG. 1, the parent ions, the quantitative ions and the qualitative ions are selected according to the invention. The method comprises the following steps: thiophene tosylate with molecular weight 282 may give rise to a molecular weight of sodium addition, equivalent to molecular weight +23, upon mass separation of the first heavy quadrupole of the mass spectrum, giving a parent ion parameter of 305m/z. After collision activation by the second tertiary rod, the parent ion is broken, and mass separation is carried out on the third tertiary rod, so that broken child ion parameters 111m/z and 195m/z can be obtained.
Scan parameter settings are as follows table 3:
table 3: scan parameter setting
Preparing a system applicability solution: taking a proper amount of thiophene tosylate reference substance, precisely weighing, placing into a 100ml volumetric flask, adding methanol for dissolution and dilution, transferring 2.0ml into the 100ml volumetric flask, adding methanol for dissolution and dilution, transferring 1.0ml into the 100ml volumetric flask, adding methanol for dissolution and dilution, and preparing a solution with the content of the thiophene tosylate of about 50ng in each 1ml as a system applicability solution.
Detection result: referring to fig. 2, it can be seen that rt=11.56 min is a peak of the thiophene tosylate quantitative ion 111m/z in this example. As a result, referring to FIG. 3, it was found that the thiophene tosylate quantitative ion 111m/z in the present example still had a signal-to-noise ratio of 1000 or more at a mass concentration of 50ng/ml, with excellent response. Referring to fig. 4, it can be seen that rt=11.56 min is a peak of 195m/z of thiophene tosylate qualitative ion in this example. From a combination of the results of FIGS. 2-4, it can be seen that thiophene tosylate has unique specificity under multiple conditions of parent ion 305m/z, quantitative ion 111m/z, and qualitative ion 195m/z.
It will be obvious to a person skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above; but that the present invention may be embodied in other specific forms without departing from its spirit or essential characteristics. Accordingly, the embodiments are to be considered in all respects as illustrative and not restrictive. The scope of the invention is indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.

Claims (4)

1. An analytical method for determining thiophene tosylate,the method is characterized in that a liquid chromatography-mass spectrometer is adopted to detect and analyze the thiophene tosylate, a liquid phase system adopts a chromatographic column with octadecylsilane chemically bonded silica as a filler, a mobile phase A is formic acid aqueous solution or acetic acid aqueous solution, a mobile phase B is methanol, the volume concentration of the mobile phase A is 0.1% -0.5%, and gradient elution is carried out; the structural formula of the thiophene tosylate isThe method comprises the steps of carrying out a first treatment on the surface of the The liquid phase system adopts column temperature of 30-50 ℃, sample injection quantity of 5-10 mu l, mobile phase flow rate of 0.5-0.9 ml/min and detection wavelength of 200-220 nm; the gradient elution procedure was:
；
the mass spectrum detector in the mass spectrum system adopts an ESI source as an ion source, and the scanning mode in the mass spectrum detector is a multi-reaction detection scanning mode; the mass spectrum detector instrument parameters are set as follows:
；
ion detection parameters in the liquid chromatography-mass spectrometer are set as follows:
。
2. the method of claim 1, wherein the column temperature is 40 ℃; the detection wavelength is 220nm.
3. The method according to claim 1, wherein the sample injection amount is 10 μl and the mobile phase flow rate is 0.7ml/min; the volume concentration of the mobile phase A is 0.1%.
4. The method of claim 1, wherein the gradient elution procedure is:
。
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