CN105067724B - A kind of detect the method for organic solvent residual in Cetilistat - Google Patents
A kind of detect the method for organic solvent residual in Cetilistat Download PDFInfo
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- CN105067724B CN105067724B CN201510472046.8A CN201510472046A CN105067724B CN 105067724 B CN105067724 B CN 105067724B CN 201510472046 A CN201510472046 A CN 201510472046A CN 105067724 B CN105067724 B CN 105067724B
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- oxolane
- dichloromethane
- toluene
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Abstract
The present invention relates to a kind of detect the method for organic solvent residual in Cetilistat, the method especially relating to simultaneously detect ethanol in Cetilistat, dichloromethane, oxolane, normal heptane, pyridine, toluene by gas chromatogram, wherein, use external standard method to detect six kinds of Determination of Residual Organic Solvents in Cetilistat simultaneously, wherein, chromatographic condition is: chromatographic column Agilent HP 5(30m*0.25mm*0.25um), column temperature 30 DEG C keeps 5 minutes, again with the ramp of 45 DEG C per minute to 200 DEG C, keep 10 minutes.Injector temperature is 200 DEG C, detects temperature 250 DEG C, carrier gas N2, split ratio 10:1, use the input mode of headspace injection method, equilibration time is 30 minutes, and equilibrium temperature is 100 DEG C；Using gas chromatography to detect the content of ethanol in Cetilistat, dichloromethane, oxolane, normal heptane, pyridine, toluene, highly sensitive, reproducible, degree of accuracy is high simultaneously；The inventive method is suitable for the detection of six kinds of organic solvent residuals in Cetilistat.
Description
Technical field
The present invention relates to a kind of detect the method for organic solvent residual in Cetilistat, especially relate to gas chromatogram with
Time detection Cetilistat in ethanol, dichloromethane, oxolane, normal heptane, pyridine, the method for Residual Toluene, belong to medicine and divide
Analysis detection field.
Background technology
Cetilistat (cetilistat) is used for obesity and complication thereof.Cetilistat is a kind of lipase inhibitor, energy
Enough activity of the lipase of suppression digestive tract and pancreatic secretion, stop intestinal absorption fat, ultimately result in weight loss, with stylish
Li Sita can also improve disease-related parameters by reducing interior fat.
Pharmacopoeia of each country is required to crude drug is carried out residual solvent inspection, to control the organic solvent used in production process
Or the residual quantity that volatile impurity is in crude drug, to ensure drug safety.The present invention is directed in Cetilistat, by synthesis technique
The ethanol of introducing, dichloromethane, oxolane, normal heptane, pyridine, six kinds of organic solvent residuals of toluene, utilize gas chromatography,
And select to detect the content of these six kinds of organic solvents under suitable chromatographic condition simultaneously.
Summary of the invention
The technical problem to be solved is to provide and a kind of detects the method for organic solvent residual in Cetilistat,
Utilize gas chromatography simplicity, fast and accurately feature, the simultaneously ethanol in detection Cetilistat, dichloromethane, tetrahydrochysene furan
Mutter, normal heptane, pyridine, six kinds of Determination of Residual Organic Solvents of toluene.
The present invention solves above-mentioned technical problem by following technical proposal.
A kind of detect the method for organic solvent residual in Cetilistat, detect second in Cetilistat by gas chromatogram simultaneously
Alcohol, dichloromethane, oxolane, normal heptane, pyridine, six kinds of Determination of Residual Organic Solvents of toluene, its step particularly as follows:
1 chromatographic condition
Chromatographic column: Agilent HP-5 (30m*0.25mm*0.25um)；
Column temperature: 30 DEG C keep 5 minutes, then with the ramp of 45 DEG C per minute to 200 DEG C, keep 10 minutes；
Injector temperature: 200 DEG C；
Detection temperature: 250 DEG C；
Carrier gas: N2, split ratio 101；
Input mode: headspace injection method；
Equilibration time: 30min；
Equilibrium temperature: 100 DEG C；
2 sample determinations, use external standard method, and it concretely comprises the following steps:
(1) system suitability
Take the mixing reference substance of ethanol, dichloromethane, oxolane, normal heptane, pyridine, toluene reference substance solution and six
Solution, respectively sample introduction, draw collection of illustrative plates；
(2) precision test
Precision measures ethanol, dichloromethane, oxolane, normal heptane, pyridine, each 10ml of toluene reference substance stock solution insert
Same 100ml measuring bottle, adds DMF to scale, shakes up, take 5ml headspace sampling.Continuous sample introduction 6 pin, note is calculated each
The RSD of reference substance peak area；
(3) linear test
Take ethanol, dichloromethane, oxolane, normal heptane, pyridine, toluene reference substance solution respectively, after equal proportion dilution,
Sample introduction, with ethanol, dichloromethane, oxolane, normal heptane, pyridine, toluene reference substance peak area as vertical coordinate, dense with six
Degree sets up linear regression curves for abscissa；
(4) recovery test
Take Cetilistat appropriate, precision weighing, it is separately added into ethanol, dichloromethane, oxolane, normal heptane, pyridine, first
Benzene reference substance solution, as response rate sample solution, sample introduction, records chromatogram, calculates the response rate；
Response rate %=(measured amount-sample size)/addition × 100%
(5) detection limit and quantitative limit test
The most respectively with N,N-dimethylformamide alcohol,diluted, dichloromethane, oxolane, normal heptane, pyridine, toluene
Reference substance solution, calculates detection limit with signal to noise ratio S/N=3, calculates quantitative limit with signal to noise ratio S/N=10；
(6) sample survey
Take Cetilistat appropriate, precision weighing, add DMF and dissolve and make need testing solution, ethanol, two
Chloromethanes, oxolane, normal heptane, pyridine, toluene reference substance solution and need testing solution sample introduction respectively, records chromatogram, presses
External standard method is with the content of ethanol, dichloromethane, oxolane, normal heptane, pyridine, toluene in calculated by peak area Cetilistat.
It is an advantage of the current invention that:
(1) use gas chromatography to detect ethanol, dichloromethane, oxolane, normal heptane, pyridine, toluene level simultaneously,
Highly sensitive, reproducible, precision is high；
(2) ethanol during the inventive method is suitable for Cetilistat, dichloromethane, oxolane, normal heptane, pyridine, toluene are residual
The detection stayed.
Accompanying drawing explanation
Fig. 1 Ethanol System compatibility test gas chromatogram (1. ethanol；2.N, dinethylformamide)
Fig. 2 dichloromethane system suitability test gas chromatogram (1. dichloromethane；2.N, dinethylformamide)
Fig. 3 oxolane system suitability test gas chromatogram (1. oxolane；2.N, dinethylformamide)
Fig. 4 n-heptane binary system compatibility test gas chromatogram (1. normal heptane；2.N, dinethylformamide)
Fig. 5 pyridine system suitability test gas chromatogram (1. pyridine；2.N, dinethylformamide)
Fig. 6 toluene system compatibility test gas chromatogram (1. toluene；2.N, dinethylformamide)
Fig. 7 ethanol, dichloromethane, oxolane, normal heptane, pyridine, toluene hybrid system compatibility test gas chromatogram
Figure (1. ethanol；2. dichloromethane；3. oxolane；4. normal heptane；5. pyridine；6. toluene；7.N, dinethylformamide)
Detailed description of the invention
Embodiment
1 instrument and reagent
Instrument: Agilent6890 gas chromatograph, detector FID；Agilent chromatographic work station；
Reagent: agents useful for same is chromatographically pure；Cetilistat (lot number: 20150601).
2 chromatographic conditions
Chromatographic column: Agilent HP-5 (30m*0.25mm*0.25um)；
Column temperature: 30 DEG C keep 5 minutes, then with the ramp of 45 DEG C per minute to 200 DEG C, keep 10 minutes；
Injector temperature: 200 DEG C；
Detection temperature: 250 DEG C；
Carrier gas: N2, split ratio 101；
Input mode: headspace injection method；
Equilibration time: 30min；
Equilibrium temperature: 100 DEG C；
3 solution preparations
Precision weighs ethanol 500mg, dichloromethane 60mg, oxolane 72mg, normal heptane 500mg, pyridine 20mg, toluene
89mg, adds DMF respectively and is dissolved in 100ml measuring bottle, and making concentration is respectively containing ethanol in every 1ml
0.5mg, dichloromethane 0.06mg, oxolane 0.072mg, normal heptane 0.5mg, pyridine 0.02mg, toluene 0.089mg molten
Liquid, as ethanol, dichloromethane, oxolane, normal heptane, pyridine, the reference substance stock solution of toluene.
Precision weighs ethanol 500mg, dichloromethane 60mg, oxolane 72mg, normal heptane 500mg, pyridine 20mg, toluene
89mg inserts same 100ml measuring bottle, adds DMF constant volume, make concentration be in every 1ml containing ethanol 0.5mg, two
Chloromethanes 0.06mg, oxolane 0.072mg, normal heptane 0.5mg, pyridine 0.02mg, the solution of toluene 0.089mg, mixing is all
Even, make mixing stock solution.
4 sample determinations
(1) system suitability
Precision measures ethanol, dichloromethane, oxolane, normal heptane, pyridine, toluene reference substance stock solution, mixes and stock
The each 10ml of liquid is respectively implanted 100mL measuring bottle, adds DMF to scale, shakes up, respectively take 5ml, headspace sampling.
Under above-mentioned chromatographic condition, each component can preferably be separated, and each component retention time and separating degree are shown in Table 1,
Accompanying drawing 1～7 is shown in by system suitability collection of illustrative plates.
Table 1 each component retention time and separating degree measurement result
(2) precision test
It is shown in Table 2.Result shows, RSD is all within 5%.
Table 2 precision test data result (n=6)
(3) linear test
Precision measures ethanol, dichloromethane, oxolane, normal heptane, pyridine, toluene reference substance stock solution, takes 5 respectively,
7.5,12.5,15ml insert 100mL measuring bottle, add DMF to scale, shake up, molten as a series of linear tests
Liquid.Headspace sampling, each solution continuous sample introduction 2 times.With reference substance peak area as vertical coordinate, ethanol, dichloromethane, tetrahydrochysene furan
Mutter, normal heptane, pyridine, toluene reference substance concentration are that abscissa sets up linear regression line.Measurement result is shown in Table 3.
Table 3 linear test measurement result
(4) recovery test
Precision weighing Cetilistat 500mg totally 9 parts, is separately added into ethanol, dichloromethane, oxolane, normal heptane, pyrrole
Pyridine, toluene reference substance stock solution 8,10,12ml insert 100ml measuring bottle, add DMF to scale, shake up, as
Response rate sample solution, takes 5ml headspace sampling.Record chromatogram, is calculated the response rate by following formula.The acceptable response rate should be
90%～110% (100% ± 10%).Measurement result is shown in Table 4.
Response rate %=(measured amount-sample size)/addition × 100%
Table 4 recovery test measurement result
(5) detection limit and quantitative limit test
With signal to noise ratio S/N=3 calculate detection limit, with signal to noise ratio S/N=10 calculate quantitative limit, the most respectively alcohol,diluted,
Dichloromethane, oxolane, normal heptane, pyridine, the reference substance stock solution of toluene.Take 5ml headspace sampling.Record chromatogram, inspection
Survey limit and quantitative limit measurement result is shown in Table 5.
Table 5 ethanol, dichloromethane, oxolane, normal heptane, pyridine, toluene detection limit, quantitative limit result
(6) sample survey result
Take Cetilistat, accurately weighed, add DMF and dissolve and make the solution containing 100mg in every 1ml,
As need testing solution.Accurate absorption ethanol, dichloromethane, oxolane, normal heptane, pyridine, toluene reference substance stock solution are each
10ml, adds DMF and is settled to 100ml measuring bottle, as reference substance solution.Accurate absorption test sample and reference substance
The each 5ml of solution, headspace sampling, record chromatogram, by external standard method with calculated by peak area, 0.5% must not be crossed containing ethanol, dichloromethane
Must not cross 0.06%, oxolane must not cross 0.072%, normal heptane must not cross 0.5%, pyridine must not cross 0.02%, toluene not
0.089% must be crossed.
According to the residual solvent of said method detection sample, ethanol 0.02%, dichloromethane 0%, oxolane 0%, positive heptan
Alkane 0%, pyridine 0%, toluene 0%.
Claims (3)
1. detecting a method for organic solvent residual in Cetilistat, detect with GC-External Standard method, its feature exists
In, detect that ethanol in Cetilistat, dichloromethane, oxolane, normal heptane, pyridine, six kinds of organic solvents of toluene are residual simultaneously
Allowance, wherein, chromatographic condition is: chromatographic column Agilent HP-5, and chromatographic column specification is 30m*0.25mm*0.25um, column temperature 30
DEG C keeping 5 minutes, then with the ramp of 45 DEG C per minute to 200 DEG C, keeps 10 minutes, injector temperature is 200 DEG C, detects
Temperature 250 DEG C, carrier gas N2, split ratio 10:1, use the input mode of headspace injection method, equilibration time is 30 minutes, balance temperature
Degree is 100 DEG C；The step of sample determination is:
The mixing reference substance taking ethanol, dichloromethane, oxolane, normal heptane, pyridine, toluene reference substance solution and six is molten
Liquid, respectively sample introduction, draw collection of illustrative plates；
Take ethanol, dichloromethane, oxolane, normal heptane, pyridine, toluene reference substance solution respectively, after equal proportion dilution, enter
Sample, with ethanol, dichloromethane, oxolane, normal heptane, pyridine, toluene reference substance peak area as vertical coordinate, with six concentration
Linear regression curves is set up for abscissa；
Take Cetilistat appropriate, precision weighing, it is separately added into ethanol, dichloromethane, oxolane, normal heptane, pyridine, toluene pair
According to product solution as response rate sample solution, sample introduction, record chromatogram, calculate the response rate；
Response rate %=(measured amount-sample size)/addition × 100%
Detection limit and quantitative limit test, the most respectively with DMF alcohol,diluted, dichloromethane, oxolane,
Normal heptane, pyridine, toluene reference substance solution, calculate detection limit with signal to noise ratio S/N=3, calculate quantitatively with signal to noise ratio S/N=10
Limit；
Take Cetilistat appropriate, precision weighing, add DMF dissolving and make need testing solution, ethanol, dichloromethane
Alkane, oxolane, normal heptane, pyridine, toluene reference substance solution and need testing solution sample introduction respectively, records chromatogram, by external standard
Method is with the content of ethanol, dichloromethane, oxolane, normal heptane, pyridine, toluene in calculated by peak area Cetilistat.
The method of organic solvent residual in detection Cetilistat the most according to claim 1, it is characterised in that use Xin Lisi
He is sample, the ethanol described in preparation, dichloromethane, oxolane, normal heptane, pyridine, toluene reference substance solution, takes second respectively
Alcohol 500mg, dichloromethane 60mg, oxolane 72mg, normal heptane 500mg, pyridine 20mg, toluene 89mg, add N, N-bis-respectively
Methylformamide is dissolved in 100ml measuring bottle, as reference substance stock solution；
Precision measures above-mentioned stock solution 10ml and inserts 100ml measuring bottle, adds DMF to scale, shakes up, make dense
Degree is for containing ethanol 0.5mg, dichloromethane 0.06mg, oxolane 0.072mg, normal heptane 0.5mg, pyridine respectively in every 1ml
0.02mg, the solution of toluene 0.089mg, molten as ethanol, dichloromethane, oxolane, normal heptane, pyridine, toluene reference substance
Liquid.
The method of organic solvent residual in detection Cetilistat the most according to claim 1, it is characterised in that described second
Alcohol, dichloromethane, oxolane, normal heptane, pyridine, the preparation of mixing reference substance solution of toluene, take ethanol, dichloromethane respectively
Alkane, oxolane, normal heptane, pyridine, each 10ml of toluene reference substance stock solution, the mixing reference substance that mix homogeneously makes six is molten
Liquid.
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| CN106770837A (en) * | 2017-01-19 | 2017-05-31 | 安徽瑞邦生物科技有限公司 | A kind of method that headspace sampling detects Residual Toluene in niacinamide |
| CN109298081B (en) * | 2017-07-24 | 2021-06-22 | 鲁南制药集团股份有限公司 | Method for determining impurity A biological sample in Cetilistat |
| CN109085277A (en) * | 2018-07-20 | 2018-12-25 | 重庆天地药业有限责任公司 | The detection method of residual solvent pyridine in a kind of cefminox sodium |
| CN109142605A (en) * | 2018-07-31 | 2019-01-04 | 湖北省宏源药业科技股份有限公司 | A kind of residual ethanol toluene pyridine limit test method in benzoic methyl nitroazole |
| CN111089911B (en) * | 2018-10-24 | 2022-09-27 | 江苏和成显示科技有限公司 | Method for detecting residual solvent in photoelectric display material |
| CN110320293B (en) * | 2019-06-28 | 2022-04-12 | 弘和制药有限公司 | Method for determining residual solvent in phthalide compound |
| CN112748204A (en) * | 2021-01-18 | 2021-05-04 | 山东盛华科技创业园有限公司 | Method for detecting content of solvent in alkyl bromobenzene products |
| CN113125602A (en) * | 2021-04-16 | 2021-07-16 | 山东铂源药业有限公司 | Method for detecting residual solvent in thujaplicin |
| CN114544844A (en) * | 2021-12-31 | 2022-05-27 | 成都新基因格生物科技有限公司 | Method for detecting dichloromethane in blood |
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| CN104374836A (en) * | 2014-09-19 | 2015-02-25 | 安徽安科生物工程（集团）股份有限公司 | HPLC determination method for Cetilistat and related impurities |
| CN104655751B (en) * | 2015-02-06 | 2016-06-15 | 山东省药学科学院 | A kind of detect the method for organic solvent residual in dapoxetine |
| CN104678017A (en) * | 2015-02-12 | 2015-06-03 | 山东省药学科学院 | Method for detecting organic-solvent residues in dabigatran etexilate |
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