CN108645933A - The gas-chromatography detection method of residual solvent in Eliquis bulk pharmaceutical chemicals - Google Patents
The gas-chromatography detection method of residual solvent in Eliquis bulk pharmaceutical chemicals Download PDFInfo
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- CN108645933A CN108645933A CN201810505946.1A CN201810505946A CN108645933A CN 108645933 A CN108645933 A CN 108645933A CN 201810505946 A CN201810505946 A CN 201810505946A CN 108645933 A CN108645933 A CN 108645933A
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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
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- G01N30/06—Preparation
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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
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Abstract
The invention discloses a kind of gas-chromatography detection method of residual solvent in Eliquis bulk pharmaceutical chemicals, feature includes following operating procedure：The preparation of test solution, mix contrast solution preparation and DMF contrast solutions preparation, detect the content for mixing residual solvent in contrast solution, test solution and DMF contrast solutions respectively using polyethylene glycol capillary column gas chromatography.The present invention establishes the capillary column gas chromatography detection method for measuring possible remaining 8 kinds of organic solvents in Eliquis bulk pharmaceutical chemicals, the results showed that, this method specificity is strong, and separating degree is good, and method is stablized, and high sensitivity is easy to operate, and accuracy is high.Linear relationship is good in the concentration range of investigation, the rate of recovery meets regulation, accurately and effectively residual solvent can be quantified, good tolerance, it is of low cost, the detection method of residual solvent in Eliquis bulk pharmaceutical chemicals is can be used as, testing result can meet outcome quality judgement, it is researched and developed suitable for laboratory, while suitable for the quality control of large-scale production.
Description
Technical field
The invention belongs to residual solvent determination methods, and in particular to the gas phase of residual solvent in Eliquis bulk pharmaceutical chemicals
Chromatographic detection method.
Background technology
Eliquis（Apixaban）A kind of direct Xa factor inhibitor of new oral, by Bristol-Myers Squibb Co. and
Pfizer's joint research and development.Currently, multiple state approvals including Eliquis Yi Huo European Union and the U.S., for reducing non-valve
The risk of property patients with atrial fibrillation apoplexy and systemic embolism.In addition, it may also be used for reduction has received to select a time hip joint or knee joint is set
The venous thromboembolism of hand-off art adult patient, the risk of deep vein thrombosis or lung thrombus, cancer patient's venous thronbosis, and
There is preferable therapeutic effect to thromboembolism.
In the synthesis and subtractive process of the bulk pharmaceutical chemicals, need to use methanol, ethyl alcohol, acetone, dichloromethane, acetic acid second
Ester, N,N-dimethylformamide（DMF）, dimethyl sulfoxide (DMSO)（DMSO）, 8 kinds of organic solvents such as formamide.These residual solvents pair
Health has certain adverse effect, needs to remove or its residual quantity is made to be no more than version in 2015《Chinese Pharmacopoeia》With ICH's
Prescribed limit.
Invention content
The present invention is provided and a kind of can only be realized in Eliquis bulk pharmaceutical chemicals by common capillary column gas chromatography instrument
The gas chromatographic detection of residual solvent.
Purpose to realize the present invention, its feature of the gas-chromatography detection method of residual solvent in this Eliquis bulk pharmaceutical chemicals
It is to include following operating procedure：
A. the DMF solution of test sample：Eliquis bulk pharmaceutical chemicals are dissolved in N,N-dimethylformamide and dimethyl sulfoxide (DMSO) respectively
In, obtain the DMSO solution of the DMF solution and test sample of the test sample that Eliquis mass concentration is 23~27mg/mL；
B. the preparation of contrast solution is mixed：By acetone, ethyl acetate, methanol, dichloromethane, ethyl alcohol, dimethyl sulfoxide (DMSO) and formyl
N,N-Dimethylformamide is separately added into amine, be configured to mass concentration be respectively 23~27mg/mL, 23~27mg/mL, 13~
The single reference substance deposit of 17mg/mL, 2.8~3.9mg/mL, 23~27mg/mL, 23~27mg/mL and 1.1~1.8mg/mL
Liquid；After again respectively mixing each single control storing solutions of 0.5~0.6mL, 190~210 times are diluted with n,N-Dimethylformamide
Obtain mixing contrast solution；
C. the preparation of DMF contrast solutions：After DMF is mixed with DMSO, it is 0.020~0.028 to be configured to DMF mass concentrations
The DMSO solution of mg/mL, that is, DMF contrast solutions；
D. it is molten above-mentioned mixing contrast solution, the DMF of test sample to be detected using polyethylene glycol capillary column gas chromatography respectively
Liquid, the DMSO solution of test sample and DMF contrast solutions, testing conditions are：
Chromatographic column：DB-WAX, 30m × 0.45mm × 0.85 μm,
Sample size：2 μ l, injector temperature：230 DEG C, split ratio：20:1,
Carrier gas：N2, flow velocity：2ml/min,
Detector：Flame ionization ditector FID, detector temperature：250 DEG C,
Temperature program：40 DEG C of initial temperature maintains 2min；50 DEG C are warming up to the rate of 2 DEG C/min, then with the speed of 20 DEG C/min
Rate is warming up to 220 DEG C, maintains 5min.
The invention has the advantages that：
1, the method for the present invention is simple and easy to do, is conducive to operation.This method uses direct injected mode, the formyl suitable for detection sample
Amine remains, and headspace sampling mode is not suitable for formamide（210 DEG C of boiling point）Detection, while direct injected need not be to solution
Carry out heating balance（Equilibration time is heated generally in 30min or so）, each sample bottle can only sample introduction one in headspace sampling mode
Secondary, sample introduction can be repeated several times in sample solution in direct injected mode, shorten preparation of samples process and detection time.
2, the method for the present invention is simple and easy to do, is suitable for the product quality control of the research and development and enterprise's large-scale production in laboratory
System.In the synthesis and subtractive process of our company Eliquis, methanol, ethyl alcohol, acetone, dichloromethane, acetic acid second can be effectively removed
The residual of the organic solvents such as ester, formamide, the residual quantity of DMF was also much smaller than version in 2015《Chinese Pharmacopoeia》It is limited with the regulation of ICH
Degree 0.5%.Only DMF residual quantities are higher（0.064%）, and version in 2015《Chinese Pharmacopoeia》With the prescribed limit 0.088% of ICH,
It needs to pay close attention to DMF.In the method, the detection for DMF need to only prepare the single contrast solution of DMF, not need
Contrast solution is prepared to other organic solvents, effectively reduces operating process and Check-Out Time, the stability of DMF contrast solutions can
Reach 10 days, further facilitates the detection to DMF residual quantities.The present invention, which establishes, to be measured in Eliquis bulk pharmaceutical chemicals and may remain
8 kinds of organic solvents capillary column gas chromatography detection method, the results showed that, this method specificity is strong, and separating degree is good, side
Method is stablized, and simple and easy to do, high sensitivity is easy to operate, and accuracy is high.Linear relationship is good in the concentration range of investigation, returns
Yield meets regulation, can accurately and effectively be quantified to residual solvent, and good tolerance is of low cost, can be used as Ah piperazine
The detection method of residual solvent in husky class's bulk pharmaceutical chemicals, testing result can meet outcome quality judgement, that is, be suitable for grinding for laboratory
Hair, while suitable for the control of product quality of enterprise's large-scale production.
Description of the drawings
Fig. 1 is present invention mixing contrast solution gas-chromatography collection of illustrative plates.
Fig. 2 is Eliquis DMF solution gas-chromatography collection of illustrative plates of the present invention.
Fig. 3 is DMF contrast solutions gas-chromatography collection of illustrative plates of the present invention.
Fig. 4 is Eliquis DMSO solution gas-chromatography collection of illustrative plates of the present invention.
Specific implementation mode
Embodiment 1：
1.1 sample preparation：
Mix the preparation of contrast solution：Precision pipettes acetone, ethyl acetate, methanol, dichloromethane, ethyl alcohol, DMSO, formyl respectively
Amine dilutes constant volume to DMF in 10mL measuring bottles, is added in right amount, shakes up, it is respectively 25.5mg/mL acetone to be configured to mass concentration
DMF solution, the DMF solution of 25.2mg/mL ethyl acetate, the DMF solution of 15.7mg/mL methanol, 3.80mg/mL dichloromethane
The DMF of DMF solution, the DMF solution of 25.3mg/mL ethyl alcohol, the DMF solution of 25.7mg/mL DMSO and 1.51mg/mL formamides
Solution, i.e., each single reference substance storing solution；It is mixed after accurate measurement each single control storing solutions of 0.5mL, is then added again
DMF dilutions shake up after being settled to 10mL, obtain mixing control storing solution；It is accurate again to measure mixing control storing solution 1.0mL, it is added
DMF dilutions shake up after being settled to 10mL, obtain mixing contrast solution；
The preparation of the DMF solution of test sample：Precision weighs Eliquis bulk pharmaceutical chemicals 250mg, sets in 10mL measuring bottles, DMF is added to dissolve
After be settled to 10mL scales, the DMF solution of test sample is obtained after shaking up；
1.2 use polyethylene glycol capillary column gas chromatographies detect above-mentioned mixing contrast solution respectively and the DMF of test sample is molten
The content of residual solvent, testing conditions are in liquid：
Chromatograph：Agilent 7890B type gas chromatographs,
Chromatographic column：DB-WAX, 30m × 0.45mm × 0.85 μm,
Sample size：2 μ l, injector temperature：230 DEG C, split ratio：20:1,
Carrier gas：N2, flow velocity：2ml/min,
Detector：Flame ionization ditector FID, detector temperature：250 DEG C,
Temperature program：40 DEG C of initial temperature maintains 2min；50 DEG C are warming up to the rate of 2 DEG C/min, then with the speed of 20 DEG C/min
Rate is warming up to 220 DEG C, maintains 5min.
6 needle of contrast solution sample introduction is mixed, peak area relative standard deviation is calculated（RSD）It is not greater than 10%, mixing control is molten
In liquid, the separating degree of measured object chromatographic peak chromatographic peak adjacent thereto should be greater than 1.5 in chromatogram, with the chromatographic peak meter of measured object
It calculates, the number of theoretical plate of capillary chromatographic column should be greater than 5000, according to external standard method to be remained in calculated by peak area testing sample solution
The content of solvent.
1.3 measurement results and conclusion
Measurement result is shown in Table 1~table 2 and Fig. 1~Fig. 2.
Conclusion：From the ＞ 1.5 equal from degree that can be seen that in table 1, table 2 in mixing contrast solution between each organic solvent, theoretical tower
Plate number is more than 5000, meets regulation.Residual solvent in Eliquis bulk pharmaceutical chemicals can be detected well by showing this method, in sample
It detects that DMSO has residual, but is much smaller than version in 2015《Chinese Pharmacopoeia》With the prescribed limit 0.5% of ICH.Typical collection of illustrative plates referring to
Fig. 1, Fig. 2.From figure 1 it appears that the method can be kept completely separate seven kinds of residual solvents, and peak type is good；It can from Fig. 2
Go out, does not detect acetone, ethyl acetate, methanol, dichloromethane, ethyl alcohol, formamide in Eliquis sample chromatogram figure, and DMSO
Peak area very little.
Embodiment 2：
2.1 sample preparation：
The preparation of DMF contrast solutions：Precision pipettes DMF in right amount in 10mL measuring bottles, adding DMSO to dilute constant volume, shakes up, is configured to
Mass concentration is the single reference substance storing solutions of 5.39mg/mL；It is accurate again to measure the single control storing solution 1.0mL of DMF, it is added
DMSO dilutions are settled to 10mL, and DMF control storing solutions are obtained after shaking up；It is accurate again to measure mixing control storing solution 1.0mL, add
Enter DMSO dilutions and be settled to 20mL, it is spare that DMF contrast solutions are obtained after shaking up；
The preparation of the DMSO solution of test sample：Precision weighs Eliquis bulk pharmaceutical chemicals 250mg, sets in 10mL measuring bottles, and DMSO is added
Dissolving, is settled to scale, the DMSO solution that test sample is obtained after shaking up is spare；
2.2 use polyethylene glycol capillary column gas chromatographies detect residual in above-mentioned mixing contrast solution and test solution respectively
The content of solvent, testing conditions is stayed to be：
Chromatograph：Agilent 7890B type gas chromatographs,
Chromatographic column：DB-WAX, 30m × 0.45mm × 0.85 μm,
Sample size：2 μ l, injector temperature：230 DEG C, split ratio：20:1,
Carrier gas：N2, flow velocity：2ml/min,
Detector：Flame ionization ditector FID, detector temperature：250 DEG C,
Temperature program：40 DEG C of initial temperature maintains 2min；50 DEG C are warming up to the rate of 2 DEG C/min, then with the speed of 20 DEG C/min
Rate is warming up to 220 DEG C, maintains 5min.
2.3 measurement results and conclusion
Measurement result is shown in Table 3~table 4 and Fig. 3~Fig. 4.
Conclusion：From in table 3, table 4 as can be seen that in DMF contrast solutions before and after the peaks DMF it is noiseless, theoretical cam curve is more than
5000, meet regulation, detects that DMF has residual in sample, but be less than version in 2015《Chinese Pharmacopoeia》It is limited with the regulation of ICH
Degree 0.088%.Typical collection of illustrative plates is referring to Fig. 3, Fig. 4.From figure 3, it can be seen that the method can detect DMF, it is front and back noiseless,
And peak type is good；Figure 4, it can be seen that detecting that DMF has residual in Eliquis sample chromatogram figure.
Claims (1)
1. the gas-chromatography detection method of residual solvent in Eliquis bulk pharmaceutical chemicals, it is characterised in that include the following steps：
A. the preparation of test solution：Eliquis bulk pharmaceutical chemicals are dissolved in N,N-dimethylformamide and dimethyl sulfoxide (DMSO) respectively
In, obtain the DMSO solution of the DMF solution and test sample of the test sample that Eliquis mass concentration is 23~27mg/mL；
B. the preparation of contrast solution is mixed：By acetone, ethyl acetate, methanol, dichloromethane, ethyl alcohol, dimethyl sulfoxide (DMSO) and formyl
N,N-Dimethylformamide is separately added into amine, be configured to mass concentration be respectively 23~27mg/mL, 23~27mg/mL, 13~
The single reference substance deposit of 17mg/mL, 2.8~3.9mg/mL, 23~27mg/mL, 23~27mg/mL and 1.1~1.8mg/mL
Liquid；After again respectively mixing each single control storing solutions of 0.5~0.6mL, 190~210 times are diluted with n,N-Dimethylformamide
Obtain mixing contrast solution；
C. the preparation of DMF contrast solutions：After DMF is mixed with DMSO, it is 0.020~0.028 to be configured to DMF mass concentrations
The DMSO solution of mg/mL, that is, DMF contrast solutions；
D. it is molten above-mentioned mixing contrast solution, the DMF of test sample to be detected using polyethylene glycol capillary column gas chromatography respectively
Liquid, the DMSO solution of test sample and DMF contrast solutions, testing conditions are：
Chromatographic column：DB-WAX, 30m × 0.45mm × 0.85 μm,
Sample size：2 μ l, injector temperature：230 DEG C, split ratio：20:1,
Carrier gas：N2, flow velocity：2ml/min,
Detector：Flame ionization ditector FID, detector temperature：250 DEG C,
Temperature program：40 DEG C of initial temperature maintains 2min；50 DEG C are warming up to the rate of 2 DEG C/min, then with the speed of 20 DEG C/min
Rate is warming up to 220 DEG C, maintains 5min.
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Cited By (2)
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| CN112114051A (en) * | 2019-06-20 | 2020-12-22 | 扬子江药业集团南京海陵药业有限公司 | Method for detecting genotoxic impurity halogenated alkane in aripiprazole |
| CN112595797A (en) * | 2021-01-05 | 2021-04-02 | 江苏嘉逸医药有限公司 | Method for determining apixaban intermediate through gas chromatography |
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Address after: 050800 No.71, Menglong street, South District, Zhengding high tech Industrial Development Zone, Zhengding District, China (Hebei) pilot Free Trade Zone, Shijiazhuang City, Hebei Province Patentee after: HEBEI CHANGSHAN BIOCHEMICAL PHARMACEUTICAL Co.,Ltd. Address before: 050800 north head of Yinchuan street, Zhengding County, Shijiazhuang City, Hebei Province Patentee before: HEBEI CHANGSHAN BIOCHEMICAL PHARMACEUTICAL Co.,Ltd. |