CN110208428A - The gas phase detection method of a variety of residual solvents in a kind of bisulfate clopidogrel bulk pharmaceutical chemicals - Google Patents
The gas phase detection method of a variety of residual solvents in a kind of bisulfate clopidogrel bulk pharmaceutical chemicals Download PDFInfo
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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
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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
- G01N30/04—Preparation or injection of sample to be analysed
- G01N2030/042—Standards
- G01N2030/047—Standards external
Abstract
The present invention provides a kind of gas phase detection methods of a variety of residual solvents in bisulfate clopidogrel bulk pharmaceutical chemicals.The gas phase detection method includes the following steps: to be injected into gas chromatograph by the way of headspace sampling by after blank solution, reference substance solution and test solution heating balance respectively, chromatogram is recorded, by external standard method with the content of calculated by peak area residual solvent；The condition of gas-chromatography are as follows: 35~45 DEG C of chromatographic column initial temperature, maintain 12~14min, rise to 165~175 DEG C with the rate of 18~22 DEG C/min, maintain 8~12min；Flame ionization ditector, 240~260 DEG C of temperature.The present invention provides a kind of gas phase analysis method of 9 kinds of residual solvents in while accurate quantitative analysis bisulfate clopidogrel bulk pharmaceutical chemicals by the preparation of selection and blank, reference substance and test solution to chromatographic condition；And high sensitivity, accuracy is high, specificity is strong, reproducibility is good, method is stable.
Description
Technical field
The present invention relates to Pharmaceutical Analysis chemical field, in particular to a variety of residuals in a kind of bisulfate clopidogrel bulk pharmaceutical chemicals
The gas phase detection method of solvent.
Background technique
Bisulfate clopidogrel (Clopidogrel Hydrogen Sulfate), No. CAS are as follows: 120202-66-6, molecule
Formula is C16H16ClNO2S·H2SO4, molecular weight are as follows: and 419.9, chemical structure are as follows:
Bisulfate clopidogrel is by a kind of platelet aggregation inhibitor of match Norfin, Inc, France exploitation, and 1998 for the first time
It is listed in the U.S. and Britain.It can selectively inhibit the combination of adenosine diphosphate (ADP) (ADP) and its platelet receptor and secondary
The activation of glycoprotein GPlllb/llla compound that mediates of ADP, therefore can inhibit platelet aggregation.
Bisulfate clopidogrel is Thienopyridines, and chemical structure is similar to ticlopidine, only on side chain
More carboxymethyls belong to anticoagulant, are mainly used for treating arteriosclerosis disease, acute coronary artery syndrome, prevention coronary artery
Restenosis and thrombotic complications etc. in stent after-poppet.Clopidogrel is the next-generation of benzyl chloride pyridine, poison
Side effect is lighter, is not resistant to patient for aspirin and is more suitble to.It is reported that its curative effect is better than similar product, and safety
Height, tolerance are good.
In the production technology of the bulk pharmaceutical chemicals, methanol, ethyl alcohol, acetone, isopropanol, methylene chloride, acetic acid may be used
9 kinds of organic solvents such as ethyl ester, n-hexane, toluene and isopropyl ether.These residual solvents have certain adverse effect to human health,
Need to be controlled the safety for guaranteeing medication in Chinese Pharmacopoeia and the prescribed limit of ICH guideline.
The patent of Publication No. CN109765304 discloses the remaining detection side of ethyl alcohol in a kind of clopidogrel bisulfate tablet
Method, this method are only capable of remaining ethyl alcohol and detect, and the residual of other organic solvents such as methanol, acetone etc. can not detect.Therefore,
Need to provide a kind of method that can be detected to a variety of organic solvent residuals in bisulfate clopidogrel raw material.
Summary of the invention
In view of this, the present invention provides a kind of vapor detections of a variety of residual solvents in bisulfate clopidogrel bulk pharmaceutical chemicals
Method.This method can 9 kinds of residual solvents in accurate quantitative analysis bisulfate clopidogrel bulk pharmaceutical chemicals simultaneously, and it is high sensitivity, accurate
Degree is high, specificity is strong, reproducibility is good, method is stable.
In order to achieve the above-mentioned object of the invention, the present invention the following technical schemes are provided:
The present invention provides a kind of gas phase detection methods of a variety of residual solvents in bisulfate clopidogrel bulk pharmaceutical chemicals, including
Following steps:
Respectively by after blank solution, reference substance solution and test solution heating balance, infused by the way of headspace sampling
Enter into gas chromatograph, chromatogram is recorded, by external standard method with the content of calculated by peak area residual solvent；
The condition of gas-chromatography are as follows:
Chromatogram column temperature: initial temperature is 35~45 DEG C, maintains 12~14min, is risen to the rate of 18~22 DEG C/min
165~175 DEG C, maintain 8~12min；
Detector: flame ionization ditector, temperature are 240~260 DEG C；
Injector temperature: 190~210 DEG C；
Carrier gas: high pure nitrogen, flow velocity are 1.0~1.5mL/min, and split ratio is (8~12): 1；
Head space condition: 60~80 DEG C of equilibrium temperature, 25~35min of heating time, 90~110 DEG C of quantitative loop temperature, transmission
100~120 DEG C of line temperature, 0.8~1.2mL of sample volume.
Preferably, the condition of gas-chromatography are as follows:
Chromatogram column temperature: initial temperature is 35~45 DEG C, maintains 13min, rises to 170 DEG C with the rate of 20 DEG C/min, dimension
Hold 10min；
Detector: flame ionization ditector, temperature are 250 DEG C；
Injector temperature: 200 DEG C；
Carrier gas: high pure nitrogen, flow velocity are 1.0~1.5mL/min, split ratio 10:1；
Head space condition: 60~80 DEG C of equilibrium temperature, 25~35min of heating time, 90~110 DEG C of quantitative loop temperature, transmission
100~120 DEG C of line temperature, sample volume 1mL.
Preferably, chromatographic column are as follows: Agilent DB-624,60m × 0.32mm × 1.8 μm.
Preferably, the initial temperature of chromatographic column is 40 DEG C.
Preferably, the flow velocity of carrier gas is 1.2mL/min.
Preferably, the equilibrium temperature in head space condition is 70 DEG C, heating time 30min, quantitative loop temperature is 100
DEG C, transmission line temperature is 110 DEG C.
Preferably, blank solution is DMF.
Preferably, reference substance solution is that methanol solution, ethanol solution, acetone soln, aqueous isopropanol, methylene chloride are molten
Liquid, ethyl acetate solution, toluene solution, hexane solution, two or more in isopropyl ethereal solution, the solvent of each solution is
DMF。
Preferably, the concentration of methanol solution is 2~4mg/mL, the concentration of ethanol solution is 4~6mg/mL, acetone soln
Concentration be 4~6mg/mL, the concentration of aqueous isopropanol is 4~6mg/mL, the concentration of dichloromethane solution is 0.04~
0.08mg/mL, the concentration of ethyl acetate solution are 4~6mg/mL, and the concentration of toluene solution is 0.8~1.0mg/mL, n-hexane
The concentration of solution is 0.2~0.4mg/mL, and the concentration of isopropyl ethereal solution is 0.8~1.2mg/mL.
Preferably, the concentration of methanol solution is 3mg/mL, and the concentration of ethanol solution is 5mg/mL, and the concentration of acetone soln is
5mg/mL, the concentration of aqueous isopropanol are 5mg/mL, and the concentration of dichloromethane solution is 0.06mg/mL, ethyl acetate solution
Concentration is 5mg/mL, and the concentration of toluene solution is 0.89mg/mL, and the concentration of hexane solution is 0.29mg/mL, isopropyl ethereal solution
Concentration be 1mg/mL.
Preferably, test solution is to contain 0.08~0.12g/mL of bisulfate clopidogrel bulk pharmaceutical chemicals, magnesium chloride
The DMF solution of 0.01~0.03g/mL.
Preferably, test solution is containing bisulfate clopidogrel bulk pharmaceutical chemicals 0.1g/mL, magnesium chloride 0.02g/mL
DMF solution.
Wherein, the effect that magnesia is added is the sulfuric acid neutralized in test solution, avoid making its in equilibrium process with
Alcohols solvent and then causes the rate of recovery relatively low if esterification occurs for methanol, ethyl alcohol and isopropanol.It should not after addition magnesia
It acutely rocks, is otherwise easy that sample solution is made to form colloidal solid, causes the rate of recovery of each solvent higher.
In the present invention, external standard method calculation formula are as follows:
In formula: the peak area at coordinative solvent peak in Ax-test solution；
The peak area at coordinative solvent peak in Ar-reference substance solution；
Cr-reference substance solution coordinative solvent concentration (mg/mL)；
Cx-test solution concentration (mg/mL).
The present invention provides a kind of gas phase detection methods of a variety of residual solvents in bisulfate clopidogrel bulk pharmaceutical chemicals.The gas
Phase detection method includes the following steps: after respectively balancing the heating of blank solution, reference substance solution and test solution, using top
The mode of empty sample introduction is injected into gas chromatograph, chromatogram is recorded, by external standard method with the content of calculated by peak area residual solvent；
The condition of gas-chromatography are as follows:
Chromatogram column temperature: initial temperature is 35~45 DEG C, maintains 12~14min, is risen to the rate of 18~22 DEG C/min
165~175 DEG C, maintain 8~12min；
Detector: flame ionization ditector, temperature are 240~260 DEG C；
Injector temperature: 190~210 DEG C；
Carrier gas: high pure nitrogen, flow velocity are 1.0~1.5mL/min, and split ratio is (8~12): 1；
Head space condition: 60~80 DEG C of equilibrium temperature, 25~35min of heating time, 90~110 DEG C of quantitative loop temperature, transmission
100~120 DEG C of line temperature, 0.8~1.2mL of sample volume.
The invention has the following advantages:
The present invention is mentioned by the test of selection and blank, reference substance and sample solution preparation method to chromatographic condition
Supplied it is a kind of can simultaneously in accurate quantitative analysis bisulfate clopidogrel bulk pharmaceutical chemicals 9 kinds of residual solvents gas phase analysis method；
The detection method of foundation is verified simultaneously.Verification result show this method high sensitivity, accuracy it is high,
Specificity is strong, reproducibility is good, method is stable, passes through the control to wherein these residual solvents that may be present, it is ensured that it is made
Drug risk is reduced to be further ensured that the safety of its preparation for the safety of bulk pharmaceutical chemicals.This method is suitable for laboratory
Research and development, while being also applied for the quality commercially produced control.
In the present invention, the effect that magnesia is added in test solution is to neutralize the sulfuric acid introduced by sample, avoids making
It is reacted with the residual solvent in sample, and the rate of recovery so as to cause the residual solvent of alcohols is relatively low.Test sample is molten simultaneously
Liquid need to avoid acutely shaking, prevent solid gel, the rate of recovery so as to cause each residual solvent is inclined after magnesia is added
It is high.
Detailed description of the invention
Fig. 1 is the chromatogram of 1 blank solution of the embodiment of the present invention；
Fig. 2 is the chromatogram of 1 reference substance solution of the embodiment of the present invention；
Fig. 3 is the chromatogram of 1 test solution of the embodiment of the present invention；
Fig. 4 is the chromatogram for the accuracy solution that 100% concentration of magnesia is not added for comparative example 1.
Specific embodiment
The invention discloses a kind of gas phase detection method of a variety of residual solvents in bisulfate clopidogrel bulk pharmaceutical chemicals, abilities
Field technique personnel can use for reference present disclosure, be suitably modified realization of process parameters.In particular, it should be pointed out that all similar replaces
Change and change apparent to those skilled in the art, they are considered as being included in the present invention.Side of the invention
Method and application be described by preferred embodiment, related personnel obviously can not depart from the content of present invention, spirit and
To method described herein and application is modified or appropriate changes and combinations in range, carry out implementation and application the technology of the present invention.
Examination used in the gas phase detection method of a variety of residual solvents in bisulfate clopidogrel bulk pharmaceutical chemicals provided by the invention
Agent or instrument are available on the market.
Below with reference to embodiment, the present invention is further explained:
Embodiment 1
1. instrument: Agilent Agilent 7890A+7697A gas chromatograph；
2. chromatographic condition:
1) chromatographic column: Agilent DB-624 (60m*0.32mm*1.8 μm), initial temperature are 40 DEG C, maintain 13min, with
The rate of 20 DEG C/min rises to 170 DEG C, maintains 10min；
2) detector: flame ionization ditector (FID), temperature are 250 DEG C；
3) injector temperature: 200 DEG C；
4) carrier gas: high pure nitrogen, flow velocity 1.2mL/min, split ratio 10:1；
5) head space condition: 70 DEG C of equilibrium temperature, heat 30min, 100 DEG C of quantitative loop temperature, 110 DEG C of transmission line temperature, into
Sample amount 1mL.
3. the preparation of blank solution:
Pipette DMF 5.0mL, in top set empty bottle, sealing, as blank solution.
4. the preparation of reference substance solution:
It is suitable that methanol, ethyl alcohol, acetone, isopropanol, methylene chloride, ethyl acetate, toluene, n-hexane, isopropyl ether are weighed respectively
It measures in 100mL volumetric flask, scale is dissolved and be diluted to DMF, is shaken up, be made 3mg containing methanol in every 1mL, ethyl alcohol 5mg, third
Ketone 5mg, isopropanol 5mg, methylene chloride 0.06mg, ethyl acetate 5mg, toluene 0.89mg, n-hexane 0.29mg and isopropyl ether 1mg
Reference substance stock solution.Precision pipettes the above-mentioned solution of 5.0mL in 50mL volumetric flask, adds DMF constant volume, mixes.Precision pipettes
Solution 5.0mL, in top set empty bottle, sealing, as reference substance solution.
5. the preparation of test solution:
Test sample about 0.5g is taken, it is accurately weighed in ml headspace bottle, DMF 5.0mL is pipetted, the dissolution of shaking several seconds is added immediately
0.1g magnesia, sealing, as test solution.
6. assay:
Above-mentioned blank solution, reference substance solution and test solution are injected into gas-chromatography by the way of headspace sampling
Instrument records chromatogram, by external standard method with calculated by peak area content.In the present invention, methanol is contained in bisulfate clopidogrel bulk pharmaceutical chemicals
It is not greater than 3000ppm, ethyl alcohol is not greater than 5000ppm, acetone is not greater than 5000ppm, isopropanol is not greater than
5000ppm, methylene chloride are not greater than 60ppm, ethyl acetate is not greater than 5000ppm, toluene is not greater than 890ppm, just oneself
Alkane is not greater than 290ppm, isopropyl ether is not greater than 5000ppm.
Calculation formula are as follows:
In formula: the peak area at coordinative solvent peak in Ax-test solution；
The peak area at coordinative solvent peak in Ar-reference substance solution；
Cr-reference substance solution coordinative solvent concentration (mg/mL)；
Cx-test solution concentration (mg/mL).
7. test result
Test result is shown in Fig. 1-3.
Test result shows that blank is noiseless, and the separating degree for compareing 9 solvent peaks in map is good, sample detection result
It complies with standard.
1 repeated experiment of test example:
The preparation of blank solution: pipetting DMF 5.0mL, in top set empty bottle, sealing, as blank solution.
The preparation of reference substance solution: methanol, ethyl alcohol, acetone, isopropanol, methylene chloride, ethyl acetate, first are weighed respectively
Benzene, n-hexane, isopropyl ether in 100mL volumetric flask, dissolve and are diluted to DMF scale, shake up in right amount, are made in every 1mL and contain
Methanol 3mg, ethyl alcohol 5mg, acetone 5mg, isopropanol 5mg, methylene chloride 0.06mg, ethyl acetate 5mg, toluene 0.89mg, just oneself
The reference substance stock solution of alkane 0.29mg and isopropyl ether 1mg.Precision pipettes the above-mentioned solution of 5.0mL in 50mL volumetric flask, adds DMF
Constant volume, mixing.Precision pipettes solution 5.0mL, in top set empty bottle, sealing, as reference substance solution.
The preparation of test solution: taking test sample about 0.5g, accurately weighed in ml headspace bottle, pipettes DMF5.0mL, shaking
0.1g magnesia, sealing, as test solution is added in several seconds dissolution immediately.
Reperformance test solution: test sample about 0.5g is taken, accurately weighed in ml headspace bottle, precision pipettes 5.0mL reference substance
0.1g magnesia, sealing, as reperformance test solution is added in solution, the dissolution of shaking several seconds immediately.
Determination of recovery rates: above-mentioned blank solution, reference substance solution, test solution and reperformance test solution are adopted respectively
Gas chromatograph is injected with the mode of headspace sampling, chromatogram is recorded, as the following formula with the calculated by peak area rate of recovery.
Calculation formula are as follows:
Following table is reperformance test rate of recovery experimental result:
1 reperformance test rate of recovery experimental result of table
Test result shows, the rate of recovery of 9 kinds of solvents between 80%~120% and RSD≤10.0%, the rate of recovery
Experimental result shows that the reproducibility of this method testing result is good.
2 accuracy of test example experiment:
The preparation of Accuracy Test Solutions: reference substance solution concentration is equivalent to according to the preparation of reference substance solution configuration method
80% is horizontal, 100% horizontal, 120% horizontal accuracy stock solution.Test sample about 0.5g is taken again, it is accurately weighed in ml headspace bottle
In, precision pipettes the above-mentioned accuracy stock solution of 5.0mL, and 0.1g magnesia, sealing, as accurate is added in the dissolution of shaking several seconds immediately
Degree test solution.The each concentration of the test solution of 3 kinds of concentration configures 3 parts.Determination of recovery rates: respectively by blank solution, reference substance
Solution, test solution and Accuracy Test Solutions inject gas chromatograph by the way of headspace sampling, record chromatogram, press
Formula is with the calculated by peak area rate of recovery.
Following table is accuracy rate of recovery experimental result:
2 accuracy rate of recovery experimental result of table
Test result shows, the rate of recovery of 9 kinds of solvents between 80%~120% and RSD≤10.0%, the rate of recovery
Experimental result shows that the accuracy of this method testing result is good.
3 Linear Experiment of test example:
The preparation of linear solvent: the range of linearity is limited to the 200% of reference substance solubility from quantifying for solvent to be measured, is respectively as follows:
Quantitative limit, 20% horizontal, 50% horizontal, 100% horizontal, 150% horizontal, 200% level.
Linear determination: the stock solution 5.0mL of above-mentioned each concentration level is taken to use the side of headspace sampling in 20mL ml headspace bottle
Formula injects gas chromatograph, and each concentration level records chromatogram into 2 needles, correlation coefficient r is calculated as follows.
By concentration successively sample introduction from low to high, using solution concentration as abscissa, using the average value of 2 needle peak areas as ordinate
Calculate regression equation.
Each solvent it is linear the result is as follows:
The 3 linear result of each solvent of table
Test result shows that the rate of recovery experimental result of linearly dependent coefficient r >=0.990 of 9 kinds of solvents shows that this method is examined
Survey the linear good of result.
Comparative example 1
Compared with Example 1, magnesia is not added in accuracy experiment.
As the result is shown: the rate of recovery of 100% concentration ethanol of accuracy is 22%, and the rate of recovery of isopropanol is 33%.
Fig. 4 is the chromatogram that 100% concentration of magnesia is not added in accuracy experiment.
The above is only a preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For member, various improvements and modifications may be made without departing from the principle of the present invention, these improvements and modifications are also answered
It is considered as protection scope of the present invention.
Claims (10)
1. the gas phase detection method of a variety of residual solvents in a kind of bisulfate clopidogrel bulk pharmaceutical chemicals, which is characterized in that including such as
Lower step:
Respectively by after blank solution, reference substance solution and test solution heating balance, it is injected by the way of headspace sampling
In gas chromatograph, chromatogram is recorded, by external standard method with the content of calculated by peak area residual solvent；
The condition of gas-chromatography are as follows:
Chromatogram column temperature: initial temperature is 35~45 DEG C, maintains 12~14min, 165 are risen to the rate of 18~22 DEG C/min~
175 DEG C, maintain 8~12min；
Detector: flame ionization ditector, temperature are 240~260 DEG C；
Injector temperature: 190~210 DEG C；
Carrier gas: high pure nitrogen, flow velocity are 1.0~1.5mL/min, and split ratio is (8~12): 1；
Head space condition: 60~80 DEG C of equilibrium temperature, 25~35min of heating time, 90~110 DEG C of quantitative loop temperature, transmission line temperature
100~120 DEG C of degree, 0.8~1.2mL of sample volume.
2. gas phase detection method according to claim 1, which is characterized in that the condition of the gas-chromatography are as follows:
Chromatogram column temperature: initial temperature is 35~45 DEG C, maintains 13min, rises to 170 DEG C with the rate of 20 DEG C/min, maintains
10min；
Detector: flame ionization ditector, temperature are 250 DEG C；
Injector temperature: 200 DEG C；
Carrier gas: high pure nitrogen, flow velocity are 1.0~1.5mL/min, split ratio 10:1；
Head space condition: 60~80 DEG C of equilibrium temperature, 25~35min of heating time, 90~110 DEG C of quantitative loop temperature, transmission line temperature
100~120 DEG C of degree, sample volume 1mL.
3. gas phase detection method according to claim 1, which is characterized in that the chromatographic column are as follows: Agilent DB-624,
60m×0.32mm×1.8μm。
4. gas phase detection method according to claim 1, which is characterized in that the initial temperature of the chromatographic column is 40 DEG C.
5. gas phase detection method according to claim 1, which is characterized in that the flow velocity of the carrier gas is 1.2mL/min.
6. gas phase detection method according to claim 1, which is characterized in that the equilibrium temperature in the head space condition is 70
DEG C, heating time 30min, quantitative loop temperature is 100 DEG C, and transmission line temperature is 110 DEG C.
7. gas phase detection method according to claim 1, which is characterized in that the blank solution is DMF.
8. gas phase detection method according to claim 1, which is characterized in that the reference substance solution is methanol solution, second
Alcoholic solution, acetone soln, aqueous isopropanol, dichloromethane solution, ethyl acetate solution, toluene solution, hexane solution, isopropyl
Two or more in ethereal solution, the solvent of each solution are DMF.
9. gas phase detection method according to claim 8, which is characterized in that the concentration of methanol solution is 2~4mg/mL, second
The concentration of alcoholic solution is 4~6mg/mL, and the concentration of acetone soln is 4~6mg/mL, and the concentration of aqueous isopropanol is 4~6mg/
ML, the concentration of dichloromethane solution are 0.04~0.08mg/mL, and the concentration of ethyl acetate solution is 4~6mg/mL, toluene solution
Concentration be 0.8~1.0mg/mL, the concentration of hexane solution is 0.2~0.4mg/mL, the concentration of isopropyl ethereal solution is 0.8~
1.2mg/mL。
10. gas phase detection method according to any one of claim 1 to 9, which is characterized in that the test solution is
DMF solution containing 0.08~0.12g/mL of bisulfate clopidogrel bulk pharmaceutical chemicals, 0.01~0.03g/mL of magnesium chloride.
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| CN113030323A (en) * | 2021-03-10 | 2021-06-25 | 山东省药学科学院 | Method for detecting residual solvent in nilotinib bulk drug |
| CN114236004A (en) * | 2021-12-16 | 2022-03-25 | 深圳万乐药业有限公司 | Method for measuring content of ethyl bromide in eptazocine hydrobromide intermediate |
| CN114527203A (en) * | 2021-12-31 | 2022-05-24 | 河北省药品医疗器械检验研究院(河北省化妆品检验研究中心) | Method for detecting residual solvent in pingyangmycin hydrochloride raw material medicine |
| CN115032313A (en) * | 2022-08-11 | 2022-09-09 | 精华制药集团南通有限公司 | Method for detecting methanol and ethanol in primidone |
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