CN107632078A - A kind of method of methyl tosylate in measure medicine - Google Patents
A kind of method of methyl tosylate in measure medicine Download PDFInfo
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- CN107632078A CN107632078A CN201710693255.4A CN201710693255A CN107632078A CN 107632078 A CN107632078 A CN 107632078A CN 201710693255 A CN201710693255 A CN 201710693255A CN 107632078 A CN107632078 A CN 107632078A
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Abstract
The present invention relates to a kind of method for determining the methyl tosylate content in medicine, and in particular to a kind of method that the methyl tosylate content in medicine is detected using headspace derivatization combined gas chromatography mass spectrometry.The derivatization method uses the mixed aqueous solution for containing vitamin C and sodium iodide as derivatization solution, its applicable equilibrium temperature and balance time range are wide, sensitivity and precision are high, accuracy is strong, durability is good and easy to operate, the Accurate Determining of the methyl tosylate in medicine can be achieved, so as to ensure Drug safety.
Description
Technical field
The invention belongs to Pharmaceutical Analysis field, and in particular to one kind uses headspace derivatization gas chromatography-mass spectrometry
To determine the method for the methyl tosylate content in medicine.
Background technology
Genotoxicity impurity is a kind of DNA reactive materials, can result in DNA damage so as to mutagenesis, and have can
Carcinogenicity can be produced to people.Based on dosage period and toxicologically safe angle, it is necessary to be paid special attention to genotoxicity impurity.
Sulphonic acid ester is a kind of potential genotoxicity impurity, and it is typically derived from low molecular alcohol and sulfonic acid or sulfonic acid halogenation
The side reaction of thing, its chemical constitution is various, including methanesulfonates such as methyl mesylate, ethyl ester, propyl ester, benzene sulfonate such as benzene sulphur
Sour methyl esters, ethyl ester, propyl ester and p-methyl benzenesulfonic acid ester such as methyl tosylate, ethyl ester and propyl ester etc..
Methyl tosylate easily hydrolyzes in aqueous environment, and the characteristic with thermally labile, is easily detecting
During decompose.In addition, under conditions of drug matrices coexist, there is also that methyl tosylate generates online shows
As.The chemical active characteristic easily decomposed and generated online online due to methyl tosylate, it is not easy to which it is right in medicine to realize
The Accurate Determining of methyl tosylate.
The content of the invention
In view of the above-mentioned problems, the change that present inventor is easily decomposed and generated online online based on methyl tosylate
Active characteristic is learned, establishes an easy headspace derivatization gas chromatography-mass spectrometry, methyl tosylate is online
It is derivative to be converted into corresponding volatile materials so as to realize detection.Applicable equilibrium temperature and the equilibration time model of the derivatization method
Enclose wide, the accurate detection of methyl tosylate in achievable medicine.
It is right in medicine so as to realize it is an object of the invention to provide a kind of headspace derivatization gas chromatography-mass spectrometry
A kind of assay of methyl tosylate (genotoxicity impurity).
Methyl tosylate contains in the detection medicine of the invention using headspace derivatization gas chromatography-mass spectrometry
Amount, wherein using the mixed aqueous solution for containing vitamin C and sodium iodide as derivatization solution.The effect of sodium iodide is by first
It is iodomethane that methyl benzene sulfonate, which derives, reflects the content of methyl tosylate by detecting the content of iodomethane；Vitamin C
Play reducing agent, prevent sodium iodide to be oxidized.The derivative reaction process is as follows：
The invention provides a kind of method for determining methyl tosylate in medicine, headspace derivatization gas phase color is used
Spectrum-MS is detected, wherein, derivatization solution is the mixed aqueous solution containing vitamin C and sodium iodide.
In the present invention, detector uses mass detector, and ion monitoring (SIM) pattern may be selected in quantitative model, with m/z
127 as the qualitative ion of auxiliary, quota ions of the m/z 142 as methyl tosylate derivative products iodomethane.
The headspace derivatization gas chromatography-mass spectrometry is detected using headspace gas chromatography-GC-MS,
Chromatographic column can use middle polarity chromatographic column (such as DB-624) or polarity chromatographic column (such as DB-WAXetr), in detection process with
35~45 DEG C are starting column temperature, keep 1~5min, and then temperature programming is to 50~100 DEG C, then temperature programming to chromatographic column most
Operation at high temperature, keep 1~10min.
The composition of the derivatization solution can be per 50.5~60.5g containing sodium iodide, vitamin in 50mL solution
C0.0005~0.005g.
Specifically, the invention provides a kind of method for determining methyl tosylate content, it comprises the following steps：
(1) prepare per 50.5~60.5g containing sodium iodide, 0.0005~0.005g of vitamin C mixing water in 50mL solution
Solution is as derivatization solution；
(2) acetonitrile is prepared with derivatization liquor capacity than 1:4~4:1 mixed solution is as blank solution；
(3) acetonitrile solution for the methyl tosylate that concentration is 0.25~1.0 μ g/mL is prepared；By p-methyl benzenesulfonic acid first
The acetonitrile solution of ester is with derivatization liquor capacity than 1:4~4:1 mixed solution compares as methyl tosylate derivatization
Solution；
(4) testing sample is dissolved in acetonitrile with derivatization liquor capacity than 1:4~4:1 mixed solution, obtain containing 0.005
The test sample derivatization solution of~0.1g/ml testing samples；
(5) isometric blank solution, methyl tosylate derivatization contrast solution and test sample derivatization are taken respectively
Solution injects headspace gas chromatography-GC-MS, according to external standard method to deduct the iodomethane calculated by peak area after blank, obtains confession
The content of methyl tosylate in test product derivatization solution.
Wherein, the blank solution, methyl tosylate derivatization contrast solution and test sample of step (5) medium volume spread out
Bio-chemical solution is respectively 1~5mL.
It is further preferable that the method for the measure methyl tosylate content, comprises the following steps：
(1) in preparing per the 50mL aqueous solution containing 59.5~60.5g of sodium iodide, 0.0006~0.0014g of vitamin C it is mixed
Heshui solution is as derivatization solution；
(2) acetonitrile is prepared with derivatization liquor capacity than 1:1 mixed solution is as blank solution；
(3) acetonitrile solution for the methyl tosylate that concentration is 0.5 μ g/mL is prepared；By the methyl tosylate
Acetonitrile solution is with derivatization solution with volume ratio 1:1 is uniformly mixed so as to obtain the methyl tosylate derivatization that concentration is 0.25 μ g/mL
Contrast solution；
(4) testing sample is dissolved in acetonitrile with derivatization liquor capacity than 1:1 mixed solution, obtain treating containing 0.01g/ml
The test sample derivatization solution of test sample product；
(5) isometric blank solution, methyl tosylate derivatization contrast solution and test sample derivatization are taken respectively
Solution injects headspace gas chromatography-GC-MS, according to external standard method to deduct the iodomethane calculated by peak area after blank, obtains confession
The content of methyl tosylate in test product derivatization solution.
In step (5), to reach vapor liquid equilibrium, each solution needs the head space in headspace gas chromatography-GC-MS
Heating balance a period of time in injector, the equilibrium temperature of head-space sampler may be selected 40~80 DEG C, and equilibration time may be selected 10
~90min.
Brief description of the drawings
Fig. 1 is blank solution mass spectrogram (m/z=142).
Fig. 2 is methyl tosylate derivatization contrast solution mass spectrogram (m/z=142).
Fig. 3 is Linear Experiment regression analysis figure.
Embodiment
Embodiments of the invention are described below in detail, it is necessary to explanation be the embodiments described below be it is exemplary, only
For explaining the present invention, and it is not considered as limiting the invention.In addition, if not clearly stating, adopted in embodiment
Reagent is that in the market can obtain.
The measure of methyl tosylate content in embodiment analog of artemisinin
1st, chromatographic condition
Instrument：Agilent 7890B gas chromatograph -5977A mass spectrograph -7697A head-space samplers
Chromatographic column：DB-Waxetr(30m×0.32mm×0.50μm)
Injector temperature：200℃
Sample size：1000μL
Split ratio：50:1
Carrier gas：Helium (constant current 2.0mL/min)
Head space condition：70 DEG C of equilibrium temperature, 90 DEG C of quantitative loop temperature, 130 DEG C of transmission line temperature, equilibration time 30min.
Column temperature：40 DEG C of holding 1min, 100 DEG C are warming up to 10 DEG C/min, are then warming up to 220 DEG C with 30 DEG C/min, dimension
Hold 3min.
Detector：Mass detector, 230 DEG C of ion source temperature, 250 DEG C of transmission line temperature.
SIM patterns (127,142)：M/z 127 spreads out as the qualitative ion of auxiliary, m/z 142 as methyl tosylate
The quota ion of biochemical products iodomethane.
2nd, experimental procedure：
(1) precision weighs sodium iodide 60.0g, vitamin C 0.001g adds pure water to dissolve and is diluted to 50mL, as derivative
Change solution；
(2) precision pipettes 1mL acetonitriles and is placed in 1mL derivatization solution in ml headspace bottle, closed to shake up, as blank solution；
(3) precision weighs methyl tosylate 0.025g, is placed in 5mL volumetric flasks, dissolves constant volume with acetonitrile；Continue to use
Acetonitrile dilutes step by step, obtains the methyl tosylate solution that concentration is 0.50 μ g/mL；It is molten to pipette 1mL methyl tosylates
Liquid, in 20mL ml headspace bottles, it is molten to obtain the methyl tosylate derivatization control that concentration is 0.25 μ g/mL with 1mL derivatizations solution
Liquid；
(4) precision weighs analog of artemisinin sample 0.02g and is placed in 20mL ml headspace bottles, adds 1mL acetonitriles and derives with 1mL
Change solution, it is closed to shake up, obtain test sample derivatization solution；
(5) respectively by blank solution, methyl tosylate derivatization contrast solution and test sample derivatization solution in top
Gas chromatograph-GC-MS, it is molten to deduct the calculated by peak area test sample derivatization of iodomethane after blank according to external standard method
The residual quantity of methyl tosylate in liquid.
Fig. 1 is blank solution mass spectrogram (m/z=142).Fig. 2 is methyl tosylate derivatization contrast solution mass spectrogram
(m/z=142).As a result show in test sample derivatization solution and do not detect methyl tosylate.
The method validation of chromatographic process
1. linear and scope
Reference substance concentrated solution is diluted step by step with acetonitrile, obtains the methyl tosylate storing solution that concentration is 5 μ g/mL；
Continue to dilute methyl tosylate storing solution step by step, it is respectively 0.008 μ g/mL, 0.15 μ g/mL, 0.30 μ g/ to obtain concentration
ML, 0.40 μ g/mL, 0.50 μ g/mL, 0.60 μ g/mL and 0.70 μ g/mL a series of linear solvents.The above-mentioned lines of 1mL are pipetted respectively
Property solution and 1mL derivatizations solution in 6 20mL ml headspace bottles, closed to shake up, it is respectively 0.004 μ g/mL, 0.075 μ to obtain concentration
G/mL, 0.15 μ g/mL, 0.20 μ g/mL, 0.25 μ g/mL, 0.30 μ g/mL and 0.35 μ g/mL methyl tosylate linearly spread out
Bio-chemical solution.1mL acetonitriles and 1mL derivatizations solution are pipetted in addition in ml headspace bottle, it is closed to shake up, as blank solution.Respectively will
The linear derivatization solution of methyl tosylate and blank solution injection chromatographic system, using m/z=142 as quota ion, warp
Blank is deducted, calculates corresponding iodomethane peak area (the following experimental results of the linear derivatization solution of methyl tosylate respectively
It is to deduct obtained by blank).With the concentration (μ g/mL) of the linear derivatization solution of methyl tosylate for abscissa (X), with iodine
Methane peak area is that ordinate (Y) carries out linear regression.As a result show methyl tosylate in the μ g/ of 0.004 μ g/mL~0.35
In the range of mL, good linear relationship, regression equation Y=42010X-144.82, R is presented with concentration in peak area2=
0.9997.Linear Experiment regression analysis figure is shown in Fig. 3.
2. repeatability
It is parallel to prepare the linear derivatization solution of methyl tosylate that 6 parts of concentration are 0.25 μ g/mL, METHOD FOR CONTINUOUS DETERMINATION, divide
Mass spectrogram is not recorded.Experimental data shows, the relative mark of the linear derivatization solution iodomethane peak area of 6 parts of methyl tosylates
Quasi- deviation is 0.37%, and the repeatability for being indicated above this method is good.
3. Intermediate precision
The linear derivatization solution of methyl tosylate that first day parallel 6 parts of concentration of preparation is 0.25 μ g/mL, second day
With parallel three parts of preparation in the 3rd day, detected according to said determination method, as a result show 12 parts of methyl tosylate lines
Property derivatization solution iodomethane peak area relative standard deviation be 1.32%, the Intermediate precision for being indicated above this method is good
It is good.
4. the rate of recovery
Precision weighs testing sample about 0.02g in 20mL ml headspace bottles, and it is 0.40 μ g/mL, 0.50 μ g/ to be separately added into concentration
ML, 0.60 μ g/mL each 1mL of methyl tosylate linear solvent, and mixed respectively with 1mL derivatization solution, it is closed
Shake up, be configured to 80%, 100% and 120% solution using 25ppm as detection concern concentration.Each concentration is parallel to prepare three
Part, test solution as the rate of recovery.By external standard method with the m/z=142 iodomethane calculated by peak area rate of recovery, result of calculation such as following table
It is shown.It can be seen that it is good to be indicated above this method rate of recovery close to 100% for the rate of recovery.
The rate of recovery test result of table 1
5. durability
The linear derivatization solution of methyl tosylate for taking concentration to be 0.25 μ g/mL, column temperature is originated by minor alteration
(+2 DEG C) and flow rate of carrier gas (+0.2mL/min) assess the durability of assay method.As a result starting column temperature and flow rate of carrier gas are shown
Small variations do not influence the measurement result of methyl tosylate, measured iodomethane peak area relative standard deviation is
1.14%, it is indicated above the good tolerance of method.
6. test limit
The linear derivatization solution of methyl tosylate is diluted step by step, mass spectrogram is recorded, when signal to noise ratio (S/N) is about 2~3
When, concentration now is minimal detectable concentration.Minimal detectable concentration is 1ng/mL.
7. quantitative limit
Dilute the linear derivatization solution of methyl tosylate step by step, record mass spectrogram, when signal to noise ratio (S/N) is about 10~
When 15, concentration now is minimum quantitative concentrations.Minimum quantitative concentrations are 4ng/mL.Method validation result is summarized and see the table below 2.
The Method validation result of table 2 is summarized
Claims (7)
1. a kind of method for determining methyl tosylate in medicine, is entered using headspace derivatization gas chromatography-mass spectrometry
Row detection, it is characterised in that：Derivatization solution is the mixed aqueous solution containing vitamin C and sodium iodide.
2. the method for methyl tosylate in medicine is determined according to claim 1, it is characterised in that：Derivatization solution
Form as 50.5~60.5g containing sodium iodide, 0.0005~0.005g of vitamin C in every 50mL solution.
3. the method for methyl tosylate in medicine is determined according to claim 1, it is characterised in that including following step
Suddenly：
(1) prepare per 50.5~60.5g containing sodium iodide, 0.0005~0.005g of vitamin C mixed aqueous solution in 50mL solution
As derivatization solution；
(2) acetonitrile is prepared with derivatization liquor capacity than 1:4~4:1 mixed solution is as blank solution；
(3) acetonitrile solution for the methyl tosylate that concentration is 0.25~1.0 μ g/mL is prepared；By methyl tosylate
Acetonitrile solution is with derivatization liquor capacity than 1:4~4:1 mixed solution is as methyl tosylate derivatization contrast solution；
(4) testing sample is dissolved in acetonitrile with derivatization liquor capacity than 1:4~4:1 mixed solution, obtain containing 0.005~
The test sample derivatization solution of 0.1g/ml testing samples；
(5) isometric blank solution, methyl tosylate derivatization contrast solution and test sample derivatization solution are taken respectively
Headspace gas chromatography-GC-MS is injected, according to external standard method to deduct the iodomethane calculated by peak area after blank, obtains test sample
The content of methyl tosylate in derivatization solution.
4. the method for methyl tosylate in medicine is determined according to claim 3, it is characterised in that including following step
Suddenly：
(1) prepare per the mixing water containing 59.5~60.5g of sodium iodide, 0.0006~0.0014g of vitamin C in the 50mL aqueous solution
Solution is as derivatization solution；
(2) acetonitrile is prepared with derivatization liquor capacity than 1:1 mixed solution is as blank solution；
(3) acetonitrile solution for the methyl tosylate that concentration is 0.5 μ g/mL is prepared；By the acetonitrile of the methyl tosylate
Solution is with derivatization solution with volume ratio 1:1, which is uniformly mixed so as to obtain the methyl tosylate derivatization that concentration is 0.25 μ g/mL, compares
Solution；
(4) testing sample is dissolved in acetonitrile with derivatization liquor capacity than 1:1 mixed solution, obtain treating test sample containing 0.01g/ml
The test sample derivatization solution of product；
(5) isometric blank solution, methyl tosylate derivatization contrast solution and test sample derivatization solution are taken respectively
Headspace gas chromatography-GC-MS is injected, according to external standard method to deduct the iodomethane calculated by peak area after blank, obtains test sample
The content of methyl tosylate in derivatization solution.
5. according to the method for methyl tosylate in the measure medicine of claim 3 or 4, it is characterised in that：In step (5)
Isometric blank solution, methyl tosylate derivatization contrast solution and test sample derivatization solution is respectively 1~5mL.
6. according to the method for methyl tosylate in the measure medicine of claim 3 or 4, it is characterised in that：In step (5)
In, equilibrium temperature is 40~80 DEG C, and equilibration time is 10~90min.
7. according to the method for methyl tosylate in the measure medicine of claim 3 or 4, it is characterised in that：Detector is adopted
Use mass detector.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108562674A (en) * | 2018-07-26 | 2018-09-21 | 淄博职业学院 | The method that derivatization HPLC-UV methods measure methanesulfonates |
| CN111505182A (en) * | 2020-05-18 | 2020-08-07 | 上海博悦生物科技有限公司 | Method for measuring dimethyl sulfate in medicine by derivatization gas chromatography-mass spectrometry |
| CN111965267A (en) * | 2020-06-30 | 2020-11-20 | 辰欣药业股份有限公司 | Method for detecting genotoxic impurity aryl sulfonate in amlodipine besylate |
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| WO2016199702A1 (en) * | 2015-06-12 | 2016-12-15 | 学校法人 東京薬科大学 | Method for evaluating cyp3a enzymatic activity in human body (phenotyping test method) |
| CN107037153A (en) * | 2017-04-21 | 2017-08-11 | 常州佳德医药科技有限公司 | The method that high performance liquid chromatography detects genotoxicity impurity in AL58805 bulk drugs or pharmaceutical preparation |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108562674A (en) * | 2018-07-26 | 2018-09-21 | 淄博职业学院 | The method that derivatization HPLC-UV methods measure methanesulfonates |
| CN108562674B (en) * | 2018-07-26 | 2021-06-15 | 淄博职业学院 | Method for measuring mesylate by derivatization HPLC-UV method |
| CN111505182A (en) * | 2020-05-18 | 2020-08-07 | 上海博悦生物科技有限公司 | Method for measuring dimethyl sulfate in medicine by derivatization gas chromatography-mass spectrometry |
| CN111965267A (en) * | 2020-06-30 | 2020-11-20 | 辰欣药业股份有限公司 | Method for detecting genotoxic impurity aryl sulfonate in amlodipine besylate |
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