CN107782820A - The assay method of genetoxic impurity ethyl p-toluenesulfonate in a kind of brufen - Google Patents
The assay method of genetoxic impurity ethyl p-toluenesulfonate in a kind of brufen Download PDFInfo
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- CN107782820A CN107782820A CN201610798559.2A CN201610798559A CN107782820A CN 107782820 A CN107782820 A CN 107782820A CN 201610798559 A CN201610798559 A CN 201610798559A CN 107782820 A CN107782820 A CN 107782820A
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- toluenesulfonate
- brufen
- ethyl
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- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 title claims abstract description 33
- VRZVPALEJCLXPR-UHFFFAOYSA-N ethyl 4-methylbenzenesulfonate Chemical compound CCOS(=O)(=O)C1=CC=C(C)C=C1 VRZVPALEJCLXPR-UHFFFAOYSA-N 0.000 title claims abstract description 32
- 239000012535 impurity Substances 0.000 title claims abstract description 10
- 238000003556 assay Methods 0.000 title claims description 4
- 239000013558 reference substance Substances 0.000 claims abstract description 46
- 239000002904 solvent Substances 0.000 claims abstract description 34
- 238000001514 detection method Methods 0.000 claims abstract description 22
- 238000000034 method Methods 0.000 claims abstract description 18
- 238000012417 linear regression Methods 0.000 claims abstract description 10
- 230000005526 G1 to G0 transition Effects 0.000 claims abstract description 3
- 239000004205 dimethyl polysiloxane Substances 0.000 claims abstract description 3
- 235000013870 dimethyl polysiloxane Nutrition 0.000 claims abstract description 3
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 claims abstract description 3
- 238000001819 mass spectrum Methods 0.000 claims abstract description 3
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 claims abstract description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 24
- 238000012360 testing method Methods 0.000 claims description 24
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 10
- 238000004949 mass spectrometry Methods 0.000 claims description 6
- ICMXUCXXGAMKJQ-UHFFFAOYSA-N C(C)OS(=O)(=O)C.C1=CC=CC=C1 Chemical compound C(C)OS(=O)(=O)C.C1=CC=CC=C1 ICMXUCXXGAMKJQ-UHFFFAOYSA-N 0.000 claims description 5
- 230000005540 biological transmission Effects 0.000 claims description 5
- 239000012159 carrier gas Substances 0.000 claims description 4
- 238000010792 warming Methods 0.000 claims description 4
- 239000001307 helium Substances 0.000 claims description 3
- 229910052734 helium Inorganic materials 0.000 claims description 3
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 239000007789 gas Substances 0.000 claims 3
- 238000002360 preparation method Methods 0.000 claims 2
- 239000000523 sample Substances 0.000 abstract description 14
- 229960001680 ibuprofen Drugs 0.000 abstract description 4
- 239000012488 sample solution Substances 0.000 abstract description 2
- 230000035945 sensitivity Effects 0.000 abstract description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract 1
- 238000003908 quality control method Methods 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 45
- 150000002500 ions Chemical class 0.000 description 15
- 238000002347 injection Methods 0.000 description 7
- 239000007924 injection Substances 0.000 description 7
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 7
- 239000003814 drug Substances 0.000 description 6
- 229940090044 injection Drugs 0.000 description 6
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 6
- 239000012895 dilution Substances 0.000 description 5
- 238000010790 dilution Methods 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 238000011084 recovery Methods 0.000 description 5
- 238000004817 gas chromatography Methods 0.000 description 4
- 230000036407 pain Effects 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- WRLRISOTNFYPMU-UHFFFAOYSA-N [S].CC1=CC=CC=C1 Chemical compound [S].CC1=CC=CC=C1 WRLRISOTNFYPMU-UHFFFAOYSA-N 0.000 description 2
- 230000036592 analgesia Effects 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 2
- 239000004744 fabric Substances 0.000 description 2
- 239000003205 fragrance Substances 0.000 description 2
- 229940088523 ibuprofen injection Drugs 0.000 description 2
- 230000036737 immune function Effects 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 description 1
- 208000022120 Jeavons syndrome Diseases 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- -1 alkyl mesylate Chemical compound 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000002924 anti-infective effect Effects 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 239000002221 antipyretic Substances 0.000 description 1
- 239000012490 blank solution Substances 0.000 description 1
- 229940083243 caldolor Drugs 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 244000000010 microbial pathogen Species 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 238000010206 sensitivity analysis Methods 0.000 description 1
- 238000012430 stability testing Methods 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 238000010200 validation analysis Methods 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
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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 provides a kind of method that combined gas chromatography mass spectrometry detects genetoxic impurity ethyl p-toluenesulfonate in brufen, mainly comprise the following steps：Use the capillary column of 5% phenyl arlydene and 95% dimethyl polysiloxane for stationary phase, prepare reference substance linear solvent and sample solution, using temperature programming, sample is after gas chromatograph separates, detected into mass detector, mass spectrum is EI sources, selects ion scan pattern to quantify, and it is m/z to select ion：91st, 92,155, with reference substance concentration and corresponding calculated by peak area equation of linear regression, and with the content of ethyl p-toluenesulfonate in equation of linear regression calculating brufen.This method is simple, quick, accurate, high sensitivity, detection method science, objective, available for the quality control of Ibuprofen samples, has practical value.
Description
Technical field
The present invention relates to one kind by genetoxic impurity in gas chromatography-mass spectrometry measure brufen to toluene sulphur
The method of acetoacetic ester.
Background technology
Brufen is a kind of non-steroid anti-inflammatory drug, its chemical name：2- methyl -4- (2- methyl-propyls) phenylacetic acid, point
Minor is：C13H18O2, molecular weight is：206.28 structural formula is：
NSAIDs (Nonsteroidal Antiinflammatory Drugs, NSAIDs) is that one kind does not contain
The anti-inflammatory agent of steroidal structure, by suppressing the synthesis of prostaglandin, its antipyretic, analgesia, antiinflammation is played, clinically extensively
ForOsteoarthritis, rheumatoid arthritis, it is a variety of heating and various pain symptoms alleviation.NSAIDs is global use at present
One of most medicament categories, the world about have 30,000,000 people using daily.Brufen can stimulate as NSAIDs
Human body and the cellular immune function of experimental animal, increase the vigor of NK, accelerate the removing of pathogenic microorganism, can be bright
It is aobvious to improve immunologic function, anti-infection ability is improved, thus there is anti-inflammatory solution hot function.Brufen is ratified for 1966 in Britain first
Listing, listed in the U.S. within 1974.Nineteen eighty-three, non-prescribed medicine is approved in Britain as first NSAIDs, it is secondary
Year is approved as non-prescribed medicine by the U.S..1985, the user of global brufen exceeded 100,000,000, had the effect of good and peace
Full property record.
U.S. FDA lists ibuprofen injection Caldolor within 2009, for alleviating gently into through intravenous infusion administration
Spend pain and as, to severe pain and treatment heating, the formulation can be not in the additional medication alleviation of opioid analgesia medicine
Energy, uncomfortable or inconvenience provide a kind of new pain relief or the selection of fever therapy using oral drugs patient.Because of Vehicles Collected from Market
On without injection stage brufen raw material, the raw material for ibuprofen injection need to be refined, allow its meet injection produce
Requirement.It can be seen from the synthesis technique of brufen, p-methyl benzenesulfonic acid is used in brufen building-up process, it is remained may be with
The ethanol synthesis generation ethyl p-toluenesulfonate used in subtractive process.European committee of drug evaluation (EMEA) correlation technique text
Part shows that alkyl mesylate impurity may have potential genetoxic, and toxicology worry threshold value (TTC) estimate is 1.5 μ
G/ people/day.Therefore, high-sensitivity analysis method need to be established and strictly controls such impurity.It is but rare on cloth Lip river in the prior art
The correlative study of the assay method of ethyl p-toluenesulfonate in sweet smell.
The content of the invention
It is an object of the invention to provide a kind of method of gas chromatography combined with mass spectrometry, detects genetoxic impurity in brufen
Ethyl p-toluenesulfonate, to control brufen material quality.
Technical scheme is as follows：
1) chromatographic condition：
GC conditions：
Chromatographic column：5% phenyl-arlydene and the capillary column that 95% dimethyl polysiloxane is stationary phase；
Post case temperature：50 DEG C~300 DEG C；
Flow velocity：0.5~1.5mL/min；
Injection port：200~300 DEG C；
Sample size：0.1~2 μ l；
Mass Spectrometry Conditions：
Detector：Mass detector：
Ion gun：EI sources, select ion scan pattern；
Ion source temperature：250~300 DEG C；
Transmission line temperature：250~300 DEG C.
2) need testing solution is appropriate with Ibuprofen samples are produced, and puts in measuring bottle, solubilizer dissolves and is diluted to scale, shakes
It is even, as need testing solution.
3) reference substance linear solvent is appropriate with ethyl p-toluenesulfonate reference substance is produced, and puts in measuring bottle, solubilizer dissolving
And dilute and reference substance storing solution is made；Precision measures in right amount respectively, and solubilizer, which quantitatively dilutes, is made a series of the molten of various concentrations
Liquid, as reference substance linear solvent.
4) measure precision measures reference substance linear solvent, is injected separately into makings chromatograph, chromatogram is recorded, with reference substance line
Property solution concentration and corresponding calculated by peak area equation of linear regression.Precision measures need testing solution, injects makings chromatograph, note
Chromatogram is recorded, is calculated by equation of linear regression to benzene methanesulfonic acid ethyl ester content.
Chromatographic column described in step 1) GC conditions is TG-5MS, length 30m, bore 0.32mm, and thickness is
0.25μm；The post case temperature uses temperature programming, 50 DEG C of initial temperature, keeps 2min, 200 are warming up to 10 DEG C/min speed
DEG C, then 300 DEG C are warming up to 30 DEG C/min speed, keep 10min；The injector temperature is preferably 280 DEG C, and input mode is
Splitless injecting samples, time 1min is not shunted；Column flow rate is preferably 1.0ml/min；Sample size in the detection method chromatographic condition
For 1 μ l.
It is m/z that ion is selected described in step 1) Mass Spectrometry Conditions：91、92、155；Ion source temperature is preferably 280 DEG C, is passed
Defeated line temperature is preferably 280 DEG C.
Further, step 2) and the 3) solvent are selected from acetone, n-hexane or its mixing.
Further, step 3) the reference substance linear solvent concentration is 20~400ng/ml.
Further, step 3) the reference substance linear solvent concentration be selected from 20,40,50,80,100,160,200,300,
400ng/ml。
Further, step 3) the reference substance linear solvent concentration be 20,40,80,160,300ng/ml.
Further, step 3) the reference substance linear solvent concentration be 40,50,100,200,400ng/ml.
Technical scheme provided by the invention, in invention research process, show ethyl p-toluenesulfonate in brufen
Clear superiority in terms of the methodology of detection.
In addition, above-mentioned detection method has been carried out Method validation by inventor.
1) specificity
Take ethyl p-toluenesulfonate reference substance appropriate, it is accurately weighed, with acetone solution and dilute be made every 1ml containing about
200ng solution, as reference substance solution；It is appropriate to weigh Ibuprofen samples, it is accurately weighed, add acetone solution and dilution is made often
Solution in 1ml containing about 0.5g, as need testing solution；Sample introduction blank solvent acetone, reference substance solution and test sample are molten respectively
Liquid, investigate the separation situation of ethyl p-toluenesulfonate and brufen.As a result show, the retention time of ethyl p-toluenesulfonate is
15.13min, the retention time of brufen is 16.22min, and blank solvent, brufen are to the measure nothing of ethyl p-toluenesulfonate
Interference.
2) linearity and range
Take ethyl p-toluenesulfonate reference substance appropriate, it is accurately weighed, every 1ml is made containing about 1mg with acetone solution and dilution
Solution, as reference substance storing solution；Precision measures in right amount, add acetone dilution be made in every 1ml respectively containing about 8,20,40,80,
200th, 400ng solution, as linear solvent.Determine in accordance with the law, using peak area as y, concentration (ng/ml) is x, is linearly returned
Return.In 20.02~400.36ng/ml concentration ranges, ethyl p-toluenesulfonate peak area and concentration are in good linear relationship,
Linear equation y=7490.7x -134488, coefficient correlation 0.9995, linear relationship is good.
3) test limit and quantitative limit
Reference substance solution is diluted step by step, is 10 to signal to noise ratio (S/N):1, it is quantitative limit；It is 3 to signal to noise ratio (S/N):When 1,
For test limit.20.5ng/ml (equivalent to 0.000004% for examination concentration) is quantitatively limited to, detection is limited to 10.3ng/ml (quite
In for examination concentration 0.000002%), much smaller than limit, meet testing requirements.
4) degree of accuracy
Precision weighs 10 parts of brufen (injection stage) sample about 5g respectively, wherein 1 part adds acetone solution and dilutes and is made often
Solution in 1ml containing about 0.5g, as blank solution.Another 9 parts are divided into 3 groups, and every group is separately added into high, medium and low three concentration
Reference substance solution, then add acetone solution and be diluted to scale, as rate of recovery need testing solution, spiked levels are respectively 100ng/
ml、200ng/ml、300ng/ml.Determine in accordance with the law respectively, the content calculated to benzene methanesulfonic acid ethyl ester is substituted into standard curve, and count
Calculate its rate of recovery.As a result show, for each concentration average recovery rate between 95%~118%, rate of recovery RSD (n=9) is 8.3%
(＜ 10%), meet test requirements document, this law accuracy is well (table 1).
The recovery test result of table 1
5) stability of solution
Ethyl p-toluenesulfonate reference substance solution is prepared, determined, investigates to toluene sulphur at 0,2,4,6,8,10 hour respectively
The situation of change of acetoacetic ester peak area simultaneously calculates RSD.As a result show, reference substance solution ethyl p-toluenesulfonate in 10 hours
Peak area shows solution-stabilized in 10 hours (table 2) without significant change (RSD=3.1%).
The solution stability testing result of table 2
| Time (hr) | 0 | 2 | 4 | 6 | 8 | 10 | RSD (%) |
| Peak area | 1245620 | 1166839 | 1156253 | 1157697 | 1141305 | 1172739 | 3.1 |
6) sample introduction precision
Ethyl p-toluenesulfonate reference substance solution is prepared, continuous sample introduction 6 times, records peak area and RSD values.As a result show,
Ethyl p-toluenesulfonate peak area is good (table 3) without significant change (RSD=2.2%), sample introduction precision in reference substance solution.
The sample introduction Precision test result of table 3
| Number of injections | 1 | 2 | 3 | 4 | 5 | 6 | RSD (%) |
| Peak area | 1390596 | 1397154 | 1380680 | 1424561 | 1454987 | 1450133 | 2.2 |
7) durability
It is appropriate to change chromatographic condition, initial temperature ± 2 DEG C, flow velocity ± 0.1ml/min, heating rate ± 1 DEG C, initial temperature keep ±
1min, brufen mark-on solution is determined, investigate ethyl p-toluenesulfonate and the separation situation at brufen peak and the change of peak area
Change.As a result show suitably to change chromatographic condition, ethyl p-toluenesulfonate can efficiently separate (separating degree ＞ with brufen peak
1.5), for ethyl p-toluenesulfonate peak area without significant change (RSD ＜ 10%), this method durability is preferable.
In summary, this method has good specificity, the linear, degree of accuracy, stability, precision and durability.
The present invention is separated using gas-chromatography, and mass spectrum selection ion scan mode quantifies, and cloth Lip river is calculated by standard curve
The content of ethyl p-toluenesulfonate in sweet smell, method take short, high sensitivity, can realize quick, accurate, batch detection.Simultaneously
This method has methodology meaning, and the instrument and equipment used is laboratory conventional analysis equipment, inventive method testing cost
It is relatively low, it is easy to spread.
Brief description of the drawings
Fig. 1 is the selection ion flow graph of ethyl p-toluenesulfonate reference substance in embodiment 1.
Fig. 2 is the mass spectrogram of ethyl p-toluenesulfonate reference substance in embodiment 1.
Fig. 3 is the selection ion flow graph of blank solvent in embodiment 1.
Fig. 4 is the canonical plotting of linear test in embodiment 1.
Fig. 5 is the selection ion flow graph of Ibuprofen samples in embodiment 1.
Embodiment
The present invention is described in further detail with reference to embodiment.These embodiments are only used for illustrating this hair
It is bright, rather than the limitation scope of the invention.
The detection of genetoxic impurity ethyl p-toluenesulfonate in the brufen of embodiment 1
1) gas-chromatography and Mass Spectrometry Conditions：
Chromatographic column：TG-5MS (30m × 0.32mm, 0.25 μm)；
Heating schedule：50 DEG C of holding 2min, rise to 200 DEG C, then rise to 300 DEG C of guarantors with 30 DEG C/min with 10 DEG C/min
Hold 10 minutes；
Carrier gas：Helium, constant current mode；
Flow velocity：1.0mL/min；
Injection port：280 DEG C, Splitless injecting samples, time 1min is not shunted；
Sample size：1μl；
MS：EI sources, ion scan pattern is selected, it is m/z to select ion：91、92、155；
Ion source temperature：280℃；
Transmission line temperature：280℃；
The solvent delay time：5min；
2) solution is prepared
Brufen 5g is taken, it is accurately weighed, put in 10ml measuring bottles, add acetone solution and be diluted to scale, shake up, as trying
Product solution.Take ethyl p-toluenesulfonate reference substance appropriate, it is accurately weighed, add acetone solution and dilution is made in every 1ml containing about 1mg
Solution, as reference substance storing solution；Precision measures in right amount, adds acetone quantitatively to dilute and is made in every 1ml respectively containing about to toluene
Sulfonic acid 40ng, 50ng, 100ng, 200ng, 400ng solution, as reference substance linear solvent.
3) detection method and result
Precision measures each 1 μ l of reference substance linear solvent, is injected separately into makings chromatograph, records chromatogram (Fig. 1~4), with
Reference substance linear solvent concentration is y=9002.6x-14981, R with corresponding calculated by peak area equation of linear regression2=
0.9989.Precision measures the μ l of need testing solution 1, injects makings chromatograph, record chromatogram (Fig. 5), based on equation of linear regression
Calculate, do not detected to benzene methanesulfonic acid ethyl ester in institute's test sample product.
The detection of genetoxic impurity ethyl p-toluenesulfonate in the brufen of embodiment 2
1) gas-chromatography and Mass Spectrometry Conditions：
Chromatographic column：TG-5MS (30m × 0.32mm, 0.25 μm)；
Heating schedule：50 DEG C of holding 2min, rise to 200 DEG C, then rise to 300 DEG C of guarantors with 30 DEG C/min with 10 DEG C/min
Hold 10 minutes；
Carrier gas：Helium, constant current mode；
Flow velocity：1.0mL/min；
Injection port：280 DEG C, Splitless injecting samples, time 1min is not shunted；
Sample size：1.0μl
MS：EI sources, ion scan pattern is selected, it is m/z to select ion：91、92、155；
Ion source temperature：280℃；
Transmission line temperature：280℃；
The solvent delay time：5min；
2) solution is prepared
Brufen 2g is taken, it is accurately weighed, put in 10ml measuring bottles, add n-hexane dissolution and be diluted to scale, shake up, as confession
Test sample solution.Take ethyl p-toluenesulfonate reference substance appropriate, it is accurately weighed, add n-hexane dissolution and dilution is made in every 1ml about
Solution containing 1mg, as reference substance storing solution；Precision measures in right amount, add n-hexane quantitatively dilute be made in every 1ml respectively containing about
Ethyl p-toluenesulfonate 20ng, 40ng, 80ng, 160ng, 300ng solution, as reference substance linear solvent.
3) detection method and result
Precision measures each 1 μ l of reference substance linear solvent, is injected separately into makings chromatograph, chromatogram is recorded, with reference substance line
Property solution concentration is y=6052.5x -97379 with corresponding calculated by peak area equation of linear regression, R2=0.9998, it is linear to close
System is good.Precision measures the μ l of need testing solution 1, injects makings chromatograph, records chromatogram, is calculated by equation of linear regression, institute
Test sample product are not detected to benzene methanesulfonic acid ethyl ester.Reference substance solution is diluted step by step, is 10 to signal to noise ratio (S/N):1, it is quantitative limit；Extremely
Signal to noise ratio (S/N) is 3:It is test limit when 1.Quantitatively it is limited to 20.0ng/ml (equivalent to 0.00001% for examination concentration), detection
10.0ng/ml (equivalent to 0.000005% for examination concentration) is limited to, test limit is less than limit with quantitative limit, meets that detection will
Ask.
Claims (10)
1. the detection method of genetoxic impurity ethyl p-toluenesulfonate in a kind of brufen, it is characterised in that methods described is gas
Phase combined gas chromatography mass spectrometry：
1) chromatographic condition：
GC conditions：
Chromatographic column：5% phenyl-arlydene and the capillary column that 95% dimethyl polysiloxane is stationary phase；
Post case temperature：50 DEG C~300 DEG C；
Carrier gas：Helium；
Flow rate of carrier gas：0.5~1.5mL/min；
Input mode：Splitless injecting samples, time 1min is not shunted；
Injector temperature：200~300 DEG C；
Sample size：0.1~2 μ l
Mass Spectrometry Conditions：
Detector：Mass detector：
Ion gun：EI sources, select ion scan pattern；
Ion source temperature：250~300 DEG C；
Transmission line temperature：250~300 DEG C；
2) preparation of need testing solution：Take brufen appropriate, solubilizer dissolving, as need testing solution；
3) preparation of reference substance linear solvent：Take ethyl p-toluenesulfonate reference substance appropriate, solubilizer is dissolved into reference substance deposit
Liquid；Solubilizer quantitatively dilutes the solution that various concentrations are made afterwards, as reference substance linear solvent；
4) assay method：Precision measures reference substance linear solvent, is injected separately into gas chromatograph-mass spectrometer (GC-MS), with reference substance line
Property solution concentration and corresponding calculated by peak area equation of linear regression；Precision measures need testing solution, injects gas chromatography-mass spectrum
Combined instrument, chromatogram is recorded, calculated by equation of linear regression to benzene methanesulfonic acid ethyl ester content.
2. detection method according to claim 1, it is characterised in that the step 1) chromatographic column is TG-5MS, and length is
30m, bore 0.32mm, thickness are 0.25 μm.
3. detection method according to claim 1, it is characterised in that the step 1) post case temperature uses temperature programming, just
Beginning temperature 50 C, 2min is kept, 200 DEG C are warming up to 10 DEG C/min speed, then 300 DEG C are warming up to 30 DEG C/min speed, protected
Hold 10min.
4. detection method according to claim 1, it is characterised in that the step 1) injector temperature is 280 DEG C, post stream
Speed is 1.0ml/min, and sample size is 1 μ l.
5. detection method according to claim 1, it is characterised in that selection ion is m/z in step 1)：91、92、155；
Ion source temperature is 280 DEG C, and transmission line temperature is 280 DEG C.
6. detection method according to claim 1, it is characterised in that step 2) and 3) solvent are selected from acetone, n-hexane
Or its mixing.
7. detection method according to claim 1, it is characterised in that step 3) the reference substance linear solvent concentration range
For 20~400ng/ml.
8. detection method according to claim 7, it is characterised in that step 3) the reference substance linear solvent concentration is selected from
20、40、50、80、100、160、200、300、400ng/ml。
9. detection method according to claim 7, it is characterised in that step 3) the reference substance linear solvent concentration be 20,
40、80、160、300ng/ml。
10. detection method according to claim 7, it is characterised in that step 3) the reference substance linear solvent concentration is
40、50、100、200、400ng/ml。
Priority Applications (1)
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| CN112326860A (en) * | 2020-10-30 | 2021-02-05 | 淄博高新技术产业开发区生物医药研究院 | Method for simultaneously detecting genotoxic impurities of 1, 4-dichlorobutane and 1-chloro-4-hydroxybutane in bulk drug or preparation |
| CN113252809A (en) * | 2021-04-25 | 2021-08-13 | 英格尔检测技术服务（上海）有限公司 | Method for detecting residues of methyl trifluoromethanesulfonate and ethyl trifluoromethanesulfonate |
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| CN109646426A (en) * | 2019-01-09 | 2019-04-19 | 成都倍特药业有限公司 | A kind of composition and 1- amino -2- propyl alcohol purity and the detection method in relation to substance |
| CN111983124A (en) * | 2020-08-25 | 2020-11-24 | 珠海润都制药股份有限公司 | Method for detecting 2, 2-dimethyl-1, 3-dichloropropane in ibuprofen |
| CN112083106A (en) * | 2020-10-09 | 2020-12-15 | 珠海润都制药股份有限公司 | Method for detecting 3-chloro-2, 2-dimethyl-1-propanol in ibuprofen |
| CN112326860A (en) * | 2020-10-30 | 2021-02-05 | 淄博高新技术产业开发区生物医药研究院 | Method for simultaneously detecting genotoxic impurities of 1, 4-dichlorobutane and 1-chloro-4-hydroxybutane in bulk drug or preparation |
| CN113252809A (en) * | 2021-04-25 | 2021-08-13 | 英格尔检测技术服务（上海）有限公司 | Method for detecting residues of methyl trifluoromethanesulfonate and ethyl trifluoromethanesulfonate |
| CN113252809B (en) * | 2021-04-25 | 2022-10-14 | 英格尔检测技术服务（上海）有限公司 | Method for detecting residues of methyl trifluoromethanesulfonate and ethyl trifluoromethanesulfonate |
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