CN108051523A - A kind of related substance detecting method of the gas-chromatography of principal component - Google Patents
A kind of related substance detecting method of the gas-chromatography of principal component Download PDFInfo
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- CN108051523A CN108051523A CN201711498105.4A CN201711498105A CN108051523A CN 108051523 A CN108051523 A CN 108051523A CN 201711498105 A CN201711498105 A CN 201711498105A CN 108051523 A CN108051523 A CN 108051523A
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- gas
- chromatography
- principal component
- related substance
- detecting method
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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
-
- 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
- G01N30/62—Detectors specially adapted therefor
- G01N30/64—Electrical detectors
- G01N30/68—Flame ionisation detectors
Abstract
The invention discloses a kind of related substance detecting methods of gas-chromatography of principal component, it is characterised in that:It is detected using gas chromatograph, areas of peak normalization method detects its purity, with 6% cyanogen propyl phenyl, 94% dimethyl polysiloxane chromatographic column filler, using hydrogen flame ionization detector, using temperature programming program, nitrogen buffer gas, gasification room temperature is 200 DEG C, 300 DEG C of detector temperature, the sample introduction by the way of split sampling.The method of the present invention specificity is strong, and stability is high, easy to operate, has filled up the blank of the prior art.
Description
Technical field
The invention belongs to pharmaceutical technology fields, are related to a kind of analysis detection of drug, particularly a kind of gas-chromatography of principal component
Related substance detecting method.
Background technology
(4R-cis) -6- aldehyde radical -2,2- dimethyl -1,3- dioxane -4- tert-butyl acetates (principal component) are that auspicious relax of synthesis is cut down
The important starting material of statin calcium, rosuvastain calcium are a kind of selective HMG-CoA reductase inhibitors, available for treating
Hyperlipidemia.It is developed by Astrazeneca AB, is listed in multiple countries and regions such as the U.S., Japan, Europe, China,
Trade name " CRESTOR ".HMG-CoA reductase inhibitor be transformation 3-hydroxy-3-methylglutaryl-coenzyme A for first valerate-
The precursor of cholesterol-rate-limiting enzyme.The main function position of Rosuvastatin is the target organs of liver-reduction cholesterol.It is auspicious
It relaxes and cuts down statin and add liver LDL cell surface receptor numbers, promote absorption and the catabolism of LDL, it is suppressed that the liver of VLDL is closed
Into, thus reduce VLDL and LDL particles sum.
(4R-cis) -6- aldehyde radical -2,2- dimethyl -1,3- dioxane -4- tert-butyl acetates, English name for (4R-cis) -
6-formaldehydel-2,2-dimethyl-1,3-dioxane-4-aceticacid,1,1-dimethylethyl
Ester, molecular formula C13H22O5, No. CAS:124752-23-4, chemical structural formula are as follows：
The adverse reaction that drug generates in Clinical practice has outside the Pass except the pharmacological activity with principal component, present in drug
Impurity also has much relations.To ensure the security of clinical application, the impurity in strictly control drug is needed.Through retrieving, at present
Have no (4R-cis) -6- aldehyde radical -2,2- dimethyl -1,3- dioxane -4- tert-butyl acetates and its Related substance method
Related patents or open source literature report.One kind (4R- is established according to the conditions such as property of its technique, catabolite, compound
Cis) analysis method of -6- aldehyde radicals -2,2- dimethyl -1,3- dioxanes -4- tert-butyl acetate purity is of great significance.
The content of the invention
It is an object of the invention to build a kind of related substance detecting method of gas-chromatography of principal component.
The present invention screens chromatographic condition, main composition can be efficiently separated with other impurities, establishes related substance
Analysis method.
Between principal component and each related substance, it can reach baseline separation between each related substance, reach the mesh of foregoing invention
's.
The invention is realized by the following technical scheme:
It is detected using gas chromatograph, areas of peak normalization method detects its purity, with -94% diformazan of 6% cyanogen propyl phenyl
Based polysiloxane chromatographic column filler, using hydrogen flame ionization detector, using temperature programming program, nitrogen buffer gas, gasification
Room temperature is 200 DEG C, 300 DEG C of detector temperature, the sample introduction by the way of split sampling.
Analysis determining method described above, chromatographic column are selected from Agilent DB-624,30mX0.53mmX3.00um
Analysis determining method described above, the one kind of described solvent in following compound:Methanol, dimethyl sulfoxide (DMSO),
Dimethylformamide, preferably methanol.
Analysis determining method of the present invention can be realized in accordance with the following methods
1) takes (4R-cis) -6- aldehyde radical -2,2- dimethyl -1,3- dioxane -4- tert-butyl acetates appropriate, is dissolved with methanol
Sample is configured to every lmL 25mg's Han (4R-cis) -6- aldehyde radical -2,2- dimethyl -1,3- dioxane -4- tert-butyl acetates
Sample solution；
2) prioritizing selections nitrogen is carrier gas, and setting flow rate of carrier gas is 3~6mL/min, optimum condition 4ml/min.With
Agilent DB-624,30mX0.53mmX3.00um are chromatographic column, and inspection sample size is 0.2~2 μ L, and optimum condition is 1 μ L, point
Flow ratio 20：1, gasification room temperature is 200 °C, and detector temperature (FID) is 300 DEG C.
3) temperature programmings are set as follows:Column temperature initial temperature is 30 DEG C, keeps 16min, rises to 180 DEG C with 20 °C/min, keeps
21.5min。
It is an advantage of the invention that：This method answers specificity good, can will likely degradation impurity, may remaining starting material and in
Mesosome is effectively separated with principal component, and high sensitivity, can be applied to (4R-cis) -6- aldehyde radical -2,2- dimethyl -1,3- dioxies oneself
The Control of Impurities of ring -4- tert-butyl acetates.
Description of the drawings：
Fig. 1 is specificity collection of illustrative plates of the present invention
Fig. 2 is quantitative limit collection of illustrative plates of the present invention
Fig. 3 is 180 DEG C of collection of illustrative plates of injection port of the present invention
Fig. 4 is present invention verification initial conditions collection of illustrative plates
Fig. 5 is 220 DEG C of collection of illustrative plates of injection port of the present invention
Fig. 6 is 270 DEG C of collection of illustrative plates of detector temperature of the present invention
Fig. 7 is 330 DEG C of collection of illustrative plates of detector temperature of the present invention
Fig. 8 is flow velocity 3.5ml/min collection of illustrative plates of the present invention
Fig. 9 is flow velocity 4.5ml/min collection of illustrative plates of the present invention
Figure 10 is 33 DEG C of collection of illustrative plates of column temperature of the present invention
Figure 11 is 37 DEG C of collection of illustrative plates of column temperature of the present invention
Specific embodiment
The methodology validation of chromatographic process of the present invention
Specificity is tested
Respectively prepare (4R-cis) -6- aldehyde radicals -2,2- dimethyl -1,3- dioxanes -4- tert-butyl acetates test solution with
And blank solvent is injected separately into gas chromatograph, records chromatogram.(4R-cis) -6- aldehyde radical -2,2- dimethyl -1,3- dioxies oneself
Ring -4- tert-butyl acetates the results are shown in Table 1 with each impurity separating degree, and collection of illustrative plates is shown in Fig. 1.
Detection method：
Instrument：Agilent 7890B high resolution gas chromatographies
Chromatographic column：Agilent DB-624,30mX0.53mmX3.00um
Gradient：Column temperature initial temperature is 30 DEG C, keeps 16min, rises to 180 DEG C with 20 DEG C/min, keeps 21.5min.
Gasify room temperature：200℃
Detector temperature：300℃
Flow velocity 4.0ml/min
Sample size：1μl
Split ratio：20：1
Table 1 (4R-cis) -6- aldehyde radical -2,2- dimethyl -1,3- dioxane -4- tert-butyl acetates and each impurity separating degree knot
Fruit, collection of illustrative plates are shown in Fig. 1~3
Conclusion：Blank solvent is noiseless to main peak, and each impurity peaks separating degree meets the requirements, noiseless to main peak.
Sample introduction precision：
Test solution continuous sample introduction 6 times calculates RSD (RSD≤10.0%) according to the result of each impurity and principal component, the result is shown in
Table 2
Detection method：
Instrument：Agilent 7890B high resolution gas chromatographies
Chromatographic column：Agilent DB-624,30mX0.53mmX3.00um
Gradient：Column temperature initial temperature is 30 DEG C, keeps 16min, rises to 180 DEG C with 20 DEG C/min, keeps 21.5min.
Gasify room temperature：200℃
Detector temperature：300℃
Flow velocity 4.0ml/min
Sample size：1μl
Split ratio：20：1
2 sample introduction Precision Experiment result of table
Conclusion：This method sample introduction precision meets the requirements.
Quantitative limit, detection limit：
Test solution is diluted into sample detection step by step
Instrument：Agilent 7890B high resolution gas chromatography instrument
Chromatographic column：Agilent DB-624,30mX0.53mmX3.00um
Gradient：Column temperature initial temperature is 30 DEG C, keeps 16min, rises to 180 DEG C with 20 DEG C/min, keeps 21.5min.
Gasify room temperature：200℃
Detector temperature：300℃
Flow velocity 4.0ml/min
Sample size：1μl
Split ratio：20：1
Quantitative limit signal-to-noise ratio is 10:Test sample concentration when 1 the results are shown in Table 3, and collection of illustrative plates is shown in Fig. 2.
3 quantitative limit of table
| Quantitative limit concentration (mg/ml) | Quantitative limit/ng | |
| Test sample | 0.0050282 | 5.0 |
Repeatability：
6 parts of (4R-cis) -6- aldehyde radical -2,2- dimethyl -1,3- dioxane -4- tert-butyl acetates test solution is prepared with method
It is injected separately into gas chromatograph,
Instrument：Agilent 7890B high resolution gas chromatographies
Chromatographic column：Agilent DB-624,30mX0.53mmX3.00um
Gradient：Column temperature initial temperature is 30 DEG C, keeps 16min, rises to 180 DEG C with 20 DEG C/min, keeps 21.5min.
Gasify room temperature：200℃
Detector temperature：300℃
Flow velocity 4.0ml/min
Sample size：1μl
Split ratio：20：1
4 iterative testing result of table
Conclusion：RSD% is respectively less than 10%, and repeatability is good.
Durability
(1) stability of solution
The decentralization of test solution room temperature is set to 0 into h, 2h, 4h, 8h, 13h distinguish sample introduction, investigate the testing result of each impurity.
5 stability of solution inspection result of table
Conclusion：Solution places 13h at normal temperatures, has good stability, and the RSD% of each impurity and principal component is respectively less than 10%
Injector temperature is changed into 180 DEG C, 220 DEG C, investigates each defects inspecting as a result, collection of illustrative plates is shown in 3-5.
Two parts of samples of parallel preparation under the conditions of each, it is each under the conditions of respectively into 1 pin, investigate defects inspecting result
6 durability of table (injector temperature ± 30 DEG C)
Conclusion：The RSD% of ± 20 DEG C of injector temperature variation, each impurity and principal component result is respectively less than 10%, good tolerance
Detector temperature is changed into 270 DEG C, 330 DEG C, investigates each defects inspecting as a result, collection of illustrative plates is shown in 6-7.
Two parts of samples of parallel preparation under the conditions of each, it is each under the conditions of respectively into 1 pin, investigate defects inspecting result
7 durability of table (detector temperature ± 30 DEG C)
Conclusion：The RSD% of ± 30 DEG C of detector temperature variation, each impurity and principal component result is respectively less than 10%, good tolerance
Flow velocity is changed into 3.5ml/min, 4.5ml/min, investigates each defects inspecting as a result, collection of illustrative plates is shown in 8-9.
Two parts of samples of parallel preparation under the conditions of each, it is each under the conditions of respectively into 1 pin, investigate defects inspecting result
8 durability of table (flow velocity ± 0.5ml/min)
Conclusion：The RSD% of change in flow ± 0.5ml/min, each impurity and principal component result is respectively less than 10%, good tolerance
Column temperature is changed into 27 DEG C, 33 DEG C, investigates each defects inspecting as a result, collection of illustrative plates is shown in 10-11.It is parallel under the conditions of each to prepare two
Part sample, it is each under the conditions of respectively into 1 pin, investigate defects inspecting result
9 durability of table (column temperature ± 3 DEG C)
Conclusion：The RSD% of ± 3 DEG C of column temperature variation, each impurity and principal component result is respectively less than 10%, good tolerance
The related substance of (4R-cis) -6- aldehyde radical -2,2- dimethyl -1,3- dioxane -4- tert-butyl acetates of empirical tests
It measures
Detection method：
Instrument：Agilent 7890B high resolution gas chromatographies instrument is equipped with hydrogen flame ionization detector
Chromatographic column：Agilent DB-624,30mX0.53mmX3.00um
Gradient：Column temperature initial temperature is 30 DEG C, keeps 16min, rises to 180 DEG C with 20 DEG C/min, keeps 21.5min.
Gasify room temperature：200℃
Detector temperature：300℃
Flow velocity 4.0ml/min
Sample size：1μl
Split ratio：20：1
The related material testing result of (4R-cis) -6- aldehyde radical -2,2- dimethyl -1,3- dioxane -4- tert-butyl acetates：
Claims (10)
1. a kind of related substance detecting method of the gas-chromatography of principal component, it is characterised in that:It is detected using gas chromatograph,
Areas of peak normalization method detects its purity, with -94% dimethyl polysiloxane chromatographic column filler of 6% cyanogen propyl phenyl, using hydrogen
Flame ionic detector, using temperature programming program, nitrogen buffer gas, gasification room temperature is 200 DEG C, detector temperature 300
DEG C, the sample introduction by the way of split sampling.
2. a kind of related substance detecting method of gas-chromatography of principal component according to claim 1, it is characterised in that：Chromatography
Column is selected from Agilent DB-624,30mX0.53mmX3.00um.
3. a kind of related substance detecting method of gas-chromatography of principal component according to claim 1, it is characterised in that：It is described
Column temperature initial temperature is 30 DEG C, keeps 16min, rises to 180 DEG C with 20 DEG C/min, keeps 21.5min..
4. a kind of related substance detecting method of gas-chromatography of principal component according to claim 1, it is characterised in that：It is described
The flow velocity of carrier gas is 2~6ml/min.
5. a kind of related substance detecting method of gas-chromatography of principal component according to claim 4, it is characterised in that：It is described
The flow velocity of carrier gas is 4ml/min.
6. a kind of related substance detecting method of gas-chromatography of principal component according to claim 1, it is characterised in that：It is described
Sample size is 0.2~2ul.
7. a kind of related substance detecting method of gas-chromatography of principal component according to claim 6, it is characterised in that：It is described
Sample size is 1ul.
8. a kind of related substance detecting method of gas-chromatography of principal component according to claim 1, it is characterised in that：It is described
Split ratio is 10：1~30:1.
9. a kind of related substance detecting method of gas-chromatography of principal component according to claim 1, it is characterised in that：It is described
Split ratio is 20:1.
10. a kind of related substance detecting method of gas-chromatography of principal component according to claim 1, it is characterised in that：Institute
Stating solvent is：One kind in methanol, dimethyl sulfoxide (DMSO), dimethylformamide.
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Cited By (2)
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| CN113433248A (en) * | 2021-07-19 | 2021-09-24 | 北京科瑞麦科技有限公司 | Preparation method of gas chromatographic column and chromatograph device with same |
| CN116381075A (en) * | 2023-02-15 | 2023-07-04 | 江苏和汇医药科技有限公司 | GC-MS (gas chromatography-mass spectrometry) -based method for detecting C0 in D5 |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113433248A (en) * | 2021-07-19 | 2021-09-24 | 北京科瑞麦科技有限公司 | Preparation method of gas chromatographic column and chromatograph device with same |
| CN113433248B (en) * | 2021-07-19 | 2022-02-08 | 北京科瑞麦科技有限公司 | Preparation method of gas chromatographic column and chromatograph device with same |
| CN116381075A (en) * | 2023-02-15 | 2023-07-04 | 江苏和汇医药科技有限公司 | GC-MS (gas chromatography-mass spectrometry) -based method for detecting C0 in D5 |
| CN116381075B (en) * | 2023-02-15 | 2024-03-12 | 江苏和汇医药科技有限公司 | GC-MS (gas chromatography-mass spectrometry) -based method for detecting C0 in D5 |
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