CN109991348A - The remaining GC detection method of triethylamine in a kind of Ai Benna peptide precursor - Google Patents
The remaining GC detection method of triethylamine in a kind of Ai Benna peptide precursor Download PDFInfo
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- CN109991348A CN109991348A CN201910188656.3A CN201910188656A CN109991348A CN 109991348 A CN109991348 A CN 109991348A CN 201910188656 A CN201910188656 A CN 201910188656A CN 109991348 A CN109991348 A CN 109991348A
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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
- G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
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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
- G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
- G01N2030/8809—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample
- G01N2030/8813—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample biological materials
Abstract
The invention discloses the remaining GC detection methods of triethylamine in a kind of Ai Benna peptide precursor, it includes that solvent is prepared, sample preparation, GC detection is carried out respectively to triethylamine reference substance solution, system suitability solution and test solution, testing conditions are as follows: 6% cyanogen propvl-phenvl-methyl polysiloxane filling chromatographic column, column temperature: 35~45 DEG C, carrier gas: nitrogen, flow velocity: 2.5~3.5ml/min, detector: FID.The present invention can accurately and effectively quantify triethylamine residual in Ai Benna peptide precursor, and operation of the present invention is easy, and testing cost is low, high sensitivity, and accuracy is high, and accurately and reliably, triethylamine is quantitatively limited to 2ppm, is far below triethylamine limit 1000ppm.Testing result can satisfy detection quality results and determine, is suitable for laboratory testing and enterprise product quality controls, can be used for the remaining detection of triethylamine in Ai Benna peptide precursor.
Description
Technical field
The present invention relates to the remaining detection methods of triethylamine in Ai Benna peptide precursor.
Background technique
GLP-1 is existing peptide hormone in a kind of human body, passes through cyclic adenosine monophosphate or other Cellular Signaling Transduction Mediated mechanism
It cooperates with and plays a role with other regulating systems, induced insulin secretion, stimulation biological insulin synthesize, glucagon suppression divides
It secretes, postpone gastric emptying and reduce food ration, while nourishing effect is generated to pancreas.
As GLP-1 analog, Exendin-4 can generate the physiology similar with GLP-1 by GLP-1 receptor-inducible and make
With, but it is more potent than GLP-1, acting duration is longer.
Ai Benna peptide precursor is a kind of Exendin-4 by synthetic modification, by being combined with recombinant human serum albumin,
It avoids fast degradation and quick kidney is removed, therefore extend acting duration, and there is the physiology similar with Exendin-4
Effect and mechanism of action.
In the purification process of Ai Benna peptide precursor, use triethylamine as mobile phase.Triethylamine has an impact to development, tool
There is genotoxicity, therefore the triethylamine in Ai Benna peptide precursor need to be remained and be controlled.
Since Ai Benna peptide precursor is precipitated using trifluoroacetic acid, cause the aqueous solution of Ai Benna peptide precursor at acidity.
Triethylamine and trifluoroacetic acid cause triethylamine not detect accurately at salt.
Summary of the invention
The present invention, which provides one kind, only can realize triethylamine in Ai Benna peptide precursor by common high resolution gas chromatography instrument
The method of residue detection.
Purpose to realize the present invention, the remaining GC detection method of triethylamine in this Ai Benna peptide precursor is it is characterized in that packet
Include following steps:
A. prepared by solution
1. reference stock solution: by triethylamine be added 0.08M~0.1M sodium hydrate aqueous solution be made concentration be 9~11mg/
The triethylamine reference stock solution of ml, it is spare；
2. reference substance solution: taking triethylamine reference stock solution that 0.08M~0.1M sodium hydrate aqueous solution is added and concentration is made
It is spare for 0.9~1.1mg/ml triethylamine reference substance solution；
3. system suitability solution: it is shaken up after the dissolution of 5ml triethylamine reference substance solution is added in Ai Benna peptide precursor 0.1g, it is standby
With；
4. test solution: after the sodium hydrate aqueous solution 5ml dissolution of 0.08M~0.1M is added in Ai Benna peptide precursor 0.1g
It shakes up, it is spare；
B. GC detects chromatographic condition
Chromatographic column: use 6% cyanogen propvl-phenvl-methyl polysiloxane for the chromatographic column of filler；Internal diameter is 0.20~0.53mm,
25~75m of column length, 1.12~3 μm of film thickness；
Column temperature: 35~45 DEG C；
Carrier gas: nitrogen；
Flow velocity: 2.5~3.5ml/min；
Detector: FID；
Injector temperature: 120~180 DEG C；
Split ratio: 20:1~30:1；
240 DEG C~280 DEG C of detector temperature；
Head space condition: 75 DEG C~85 DEG C of head space equilibrium temperature；
Head space equilibration time: 25~35min；
Temperature program: being warming up to 100 DEG C after 40 DEG C of 6~10min of holding with 10~20 DEG C/min, keeps after 1~3min again with 20
~40 DEG C/min heating DEG C, keeps 1~3min after being warming up to 180 DEG C；Finally 240 DEG C are risen to 30 DEG C/min, maintain 7~
9min；
C. gas chromatograph detection is carried out to blank solvent, system suitability solution, reference substance solution, test solution.
The selection of chromatographic condition of the present invention
1, the selection of chromatographic column
The present invention selects tri- kinds of gas chromatographic columns of HP-5, DB-624, HP-50 respectively, is divided with detection time 55 when HP-5 chromatographic column
Clock, with chromatographic peak bifurcated when HP-50 chromatographic column.It by comparing, is filler with 6% cyanogen propvl-phenvl-methyl polysiloxane
Chromatographic column effect is best, and tailing factor, accuracy and durability of triethylamine etc. are best.
2, the selection of column temperature
It selects 6% cyanogen propvl-phenvl-methyl polysiloxane to carry out triethylamine for the chromatographic column of filler and detects optimum temperature use
35~180 DEG C of range.
3, the selection of head space equilibrium temperature
The solvent that the present invention uses is 0.08M~0.1M sodium hydrate aqueous solution, head space equilibrium temperature optimum temperature use scope
It is 75 DEG C~85 DEG C.
The foundation of the method for the present invention
1, specificity is tested
After 0.08M~0.1M sodium hydrate aqueous solution blank solvent, the difference head space heating of system suitability solution, it is implanted sequentially
Gas chromatograph records chromatogram, and spectrogram shows that solvent is noiseless to detecting, and the separating degree between triethylamine and other impurities is greater than
1.5。
2, the range of linearity
Precision measures that triethylamine control stock solution is each 1,2.5,4,5,6,7.5ml, is respectively placed in 6 50ml volumetric flasks, solubilization
Dilution agent shakes up rear each accurate measurement 5ml, is respectively placed in 20ml ml headspace bottle, gland, injects gas phase after head space heating to scale
Chromatograph records chromatogram.With peak area (A) be ordinate, concentration (C) be abscissa carry out linear regression, regression equation A=
54561C 1372.6, r2=0.9982(n=6), the results showed that triethylamine has good within the scope of 0.2048~1.5362mg/ml
Good linear relationship.
3, serviceability test
3.1 different chromatographic columns
It selects the chromatographic column of three different lot numbers to carry out system suitability and Ai Benna peptide precursor is measured, system is suitable
It is met the requirements with property test, triethylamine measurement result is consistent, the results are shown in Table 1, from investigation result it is found that the chromatography of different lot numbers
Column is all satisfied measurement and requires.
Triethylamine assay difference chromatographic column investigates result in 1 Ai Benna peptide precursor of table
DB-624 chromatographic column is U.S. Agilent Products, and filler is 6% cyanogen propvl-phenvl-methyl polysiloxane.
3.2 different chromatographic conditions are investigated
Chromatographic condition in appropriate change Ai Benna peptide precursor when triethylamine assay, carries out system suitability and to Chinese mugwort
This that peptide precursor is measured, and system suitability meets the requirements, and triethylamine measurement result is consistent, the chromatographic condition of confirmation
Durability range and triethylamine measurement result be shown in Table 2, table 3.
The durability of 2 triethylamine of table inspection chromatographic condition
The measurement result of triethylamine difference chromatographic condition in 3 Ai Benna peptide precursor of table
4, accuracy
Test sample Ai Benna peptide precursor 0.1g is taken, after accurately weighed, is placed in 20ml ml headspace bottle, 5ml contrast solution is added in precision
After dissolution, gland is shaken up.Parallel 6 parts of preparation, respectively head space heating, injects gas chromatograph, records chromatogram.Calculate three second
The rate of recovery of amine, triethylamine rate of recovery range is 94.31~100.24%, rate of recovery RSD(n=6) 2.08%, it the results are shown in Table 4.
4 accuracy result of table
5, quantitative limit
Take triethylamine reference substance stock solution appropriate, the sodium hydrate aqueous solution that 0.08M~0.1M is added is diluted to the concentration of 2ppm
Afterwards, accurate to measure 5ml, it is placed in gland in 20ml ml headspace bottle, is shaken up.Head space heating, injects gas chromatograph, records chromatogram,
Signal-to-noise ratio S/N is 1626 at this time, peak area RSD%(n=6) it is 5.2%.Sample introduction concentration 2ppm(is equivalent to principal component Chinese mugwort originally at this time
The 0.01% of that peptide precursor mass content), meet triethylamine testing requirements.
The results show that using 6% cyanogen propvl-phenvl-methyl polysiloxane is the gas chromatographic column of filler by above-mentioned condition
The content of triethylamine in Ai Benna peptide precursor is measured, verified method is accurately feasible.
The invention has the following advantages:
(1) sodium hydroxide is added makes test solution show slightly alkalinity, can meet testing requirements, sample detection time is short, single needle sample
Product runing time about 26min, it is easy to operate reliable, it is low to chromatographic column and instrument requirements, it is not only suitable for the detection in laboratory, it is more suitable
For the control of product quality of enterprise's large-scale production, testing result can comparatively fast be obtained for control etc. in product.
(2) the method for the present invention specificity is strong, and the accuracy rate of recovery is between 94.31%~100.24%, linear coefficient r2For
0.9982, it can triethylamine content in Accurate Determining acidic sample.
(3) the method for the present invention is quantitatively limited to 2ppm, and detection is sensitiveer, and is far below limit value, can effectively detect Chinese mugwort originally
Triethylamine residual quantity in that peptide precursor may be applicable to the product for carrying out triethylamine residue detection in acidic sample.
Detailed description of the invention
Fig. 1 is the blank solvent chromatic graph spectrum of triethylamine in present invention detection Ai Benna peptide precursor.
Fig. 2 is the system suitability solution chromatic graph spectrum of triethylamine in present invention detection Ai Benna peptide precursor.
Fig. 3 is the reference substance solution chromatogram of triethylamine in present invention detection Ai Benna peptide precursor.
Fig. 4 is the test solution chromatogram of triethylamine in present invention detection Ai Benna peptide precursor.
Specific embodiment
Following embodiment facilitates understanding of the invention, but these embodiments are only for being illustrated the present invention, this hair
It is bright to be not limited to these contents.
Embodiment 1:
In Ai Benna peptide precursor triethylamine content measurement the following steps are included:
A. prepared by solution
1. reference stock solution: the sodium hydrate aqueous solution for taking triethylamine about 1g that 0.08M is added into 100ml volumetric flask is made
Concentration is 9~11mg/ml triethylamine reference stock solution, spare；
2. reference substance solution: taking above-mentioned triethylamine reference substance stock solution 10ml that the hydrogen-oxygen of 0.08M is added into 100ml volumetric flask
Change sodium water solution, constant volume shakes up, and it is 0.9~1.1mg/ml triethylamine reference substance solution that concentration, which is made, spare；
3. system suitability solution: it is shaken up after taking Ai Benna peptide precursor 0.1g that the dissolution of 5ml triethylamine reference substance solution is added, it is standby
With；
4. test solution: taking Ai Benna peptide precursor test sample 0.1g, the sodium hydrate aqueous solution 5ml that 0.08M is added in precision is molten
It is shaken up after solution, it is spare；
B. GC detects chromatographic condition
Chromatograph: 7890 type gas chromatograph of Agilent is used；
Chromatographic column: use 6% cyanogen propvl-phenvl-methyl polysiloxane for the chromatographic column of filler；Internal diameter is 0.53mm, column length
30m, 3 μm of film thickness；
Chromatographic condition:
Chromatograph: 7890 type gas chromatograph of Agilent；
Column temperature: 40 DEG C；
Carrier gas: nitrogen；
Flow velocity: 3.0ml/min；
Detector: FID；
Injector temperature: 150 DEG C；
Split ratio: 25:1；
260 DEG C of detector temperature；
Head space condition: 80 DEG C of head space equilibrium temperature；
Head space equilibration time: 30min；
Chromatographic column temperature program: being warming up to 100 DEG C after 40 DEG C of holding 8min with 20 DEG C/min, keeps 1min；Again with 30 DEG C/min
2min is kept after being warming up to 180 DEG C, maintains 8min after finally rising to 240 DEG C with 30 DEG C/min；
C. blank solvent, system suitability solution, reference substance solution, test solution are subjected to gas chromatograph detection respectively.
D. measurement result
1. system suitability result
Triethylamine retention time is 10.192 min, tailing factor 1.40, theoretical cam curve 72493, point with adjacent chromatographic peak
It is 68.07 from degree.
0.08M~0.1M sodium hydrate aqueous solution blank solvent is injected into gas chromatograph, records chromatogram such as Fig. 1 institute
Show, as can be seen from Figure 1, the sodium hydrate aqueous solution of 0.08M~0.1M is on the detection of triethylamine in Ai Benna peptide precursor without influence.
System suitability solution is injected into gas chromatograph, record chromatogram is as shown in Fig. 2, as can be seen from Figure 2, triethylamine
Separating degree between other impurities is greater than 1.5, and impurity is on the detection of triethylamine in Ai Benna peptide precursor without influence.
2. test sample is tested
Above-mentioned test solution and reference substance solution is taken to be injected separately into gas chromatograph, record chromatogram is as shown in Figure 3,4, from figure
3 can be seen that, triethylamine chromatographic peak peak type is good, consistent in retention time and system suitability solution, before can be used for Ai Benna peptide
The detection of triethylamine in body；As can be seen from Figure 4, triethylamine is not detected in test sample, it is seen that in Ai Benna peptide precursor preparation process
In, triethylamine has removed the requirement for completely meeting the genetoxic limit of impurities.
E. calculated result
Wherein: MIt is right: the quality (mg) of triethylamine reference substance；
VIt is right: the dilution volume (ml) of triethylamine reference substance solution；
PIt is right: the purity (99.99%) of triethylamine reference substance；
AFor: the chromatographic peak area of triethylamine in test solution；
MFor: the quality (mg) of test sample Ai Benna peptide precursor；
VFor: the dilution volume (ml) of test sample Ai Benna peptide precursor solution；
AIt is right: the chromatographic peak area of triethylamine in reference substance.
In Ai Benna peptide precursor:
=0,
Triethylamine residual is not detected in Ai Benna peptide precursor.
Embodiment 2:
A. prepared by solution
1. reference stock solution: the sodium hydrate aqueous solution for taking triethylamine about 1g that 0.1M is added into 100ml volumetric flask is made
Concentration is 9~11mg/ml triethylamine reference stock solution, spare；
2. reference substance solution: taking above-mentioned triethylamine reference substance stock solution 10ml that the hydrogen-oxygen of 0.1M is added into 100ml volumetric flask
Change sodium water solution, constant volume shakes up, and it is 0.9~1.1mg/ml triethylamine reference substance solution that concentration, which is made, spare；
3. system suitability solution: it is shaken up after taking Ai Benna peptide precursor 0.1g that the dissolution of 5ml triethylamine reference substance solution is added, it is standby
With；
4. test solution: taking Ai Benna peptide precursor test sample 0.1g, the sodium hydrate aqueous solution 5ml dissolution of 0.1M is added in precision
After shake up, it is spare；
B. GC detects chromatographic condition
Chromatograph: 7890 type gas chromatograph of Agilent is used；
Chromatographic column: use 6% cyanogen propvl-phenvl-methyl polysiloxane for the chromatographic column of filler；Internal diameter is 0.53mm, column length
30m, 3 μm of film thickness；
Chromatographic condition:
Chromatograph: 7890 type gas chromatograph of Agilent；
Column temperature: 40 DEG C；
Carrier gas: nitrogen；
Flow velocity: 3.0ml/min；
Detector: FID；
Injector temperature: 150 DEG C；
Split ratio: 25:1；
260 DEG C of detector temperature；
Head space condition: 80 DEG C of head space equilibrium temperature；
Head space equilibration time: 30min；
Chromatographic column temperature program: being warming up to 100 DEG C after 40 DEG C of holding 8min with 20 DEG C/min, keeps 1min；Again with 30 DEG C/min
2min is kept after being warming up to 180 DEG C, maintains 8min after finally rising to 240 DEG C with 30 DEG C/min.
C. sample detection and result
Vapor detection blank solvent, system suitability solution, reference substance solution, test solution detection are carried out according to the above method,
It the results are shown in Table 5.
5 Ai Benna peptide precursor testing result (sodium hydrate aqueous solution of 0.1M) of table
As can be seen from Table 5, change sample dissolution solvent, do not make significant difference to the detection of triethylamine, system suitability solution
Middle triethylamine peak area is 61873 very close with triethylamine peak area 61370 in reference substance solution, indicates the triethylamine rate of recovery
Well.Triethylamine is not detected in test sample.
Embodiment 3:
A. prepared by solution
1. reference stock solution: the sodium hydrate aqueous solution for taking triethylamine about 1g that 0.08M is added into 100ml volumetric flask is made
Concentration is 9~11mg/ml triethylamine reference stock solution, spare；
2. reference substance solution: taking above-mentioned triethylamine reference substance stock solution 10ml that the hydrogen-oxygen of 0.08M is added into 100ml volumetric flask
Change sodium water solution, constant volume shakes up, and it is 0.9~1.1mg/ml triethylamine reference substance solution that concentration, which is made, spare；
3. system suitability solution: it is shaken up after taking Ai Benna peptide precursor 0.1g that the dissolution of 5ml triethylamine reference substance solution is added, it is standby
With；
4. test solution: taking Ai Benna peptide precursor test sample 0.1g, the sodium hydrate aqueous solution 5ml that 0.08M is added in precision is molten
It is shaken up after solution, it is spare；
B. GC detects chromatographic condition
Chromatograph: 7890 type gas chromatograph of Agilent is used；
Chromatographic column: use 6% cyanogen propvl-phenvl-methyl polysiloxane for the chromatographic column of filler；Internal diameter is 0.53mm, column length
30m, 3 μm of film thickness；
Chromatographic condition:
Chromatograph: 7890 type gas chromatograph of Agilent；
Column temperature: 40 DEG C；
Carrier gas: nitrogen；
Flow velocity: 3.5ml/min；
Detector: FID；
Injector temperature: 150 DEG C；
Split ratio: 25:1；
260 DEG C of detector temperature；
Head space condition: 80 DEG C of head space equilibrium temperature；
Head space equilibration time: 30min；
Chromatographic column temperature program: being warming up to 100 DEG C after 40 DEG C of holding 8min with 20 DEG C/min, keeps 1min；Again with 30 DEG C/min
2min is kept after being warming up to 180 DEG C, maintains 8min after finally rising to 240 DEG C with 30 DEG C/min.
C. sample detection and result
Vapor detection blank solvent, system suitability solution, reference substance solution, test solution detection are carried out according to the above method,
It the results are shown in Table 6.
6 Ai Benna peptide precursor testing result (flow velocity: 3.5ml/min) of table
As can be seen from Table 6, triethylamine and the minimum separation degree of other impurities are 62.15(separating degree in system suitability solution
> 1.5), tailing factor meets regulation between 0.8~2.0.Before showing that suitably changing chromatographic condition not influences Ai Benna peptide
The detection of triethylamine in body.
Claims (1)
1. the remaining GC detection method of triethylamine in a kind of Ai Benna peptide precursor, it is characterised in that the following steps are included:
Solution preparation
1. reference stock solution: it is 9~11mg/ that triethylamine, which is added 0.08M~0.1M sodium hydrate aqueous solution concentration is made,
The triethylamine reference stock solution of ml, it is spare；
2. reference substance solution: taking triethylamine reference stock solution that 0.08M~0.1M sodium hydrate aqueous solution is added and concentration is made
It is spare for 0.9~1.1mg/ml triethylamine reference substance solution；
3. system suitability solution: it is shaken up after the dissolution of 5ml triethylamine reference substance solution is added in Ai Benna peptide precursor 0.1g, it is standby
With；
4. test solution: after the sodium hydrate aqueous solution 5ml dissolution of 0.08M~0.1M is added in Ai Benna peptide precursor 0.1g
It shakes up, it is spare；
B. GC detects chromatographic condition
Chromatographic column: use 6% cyanogen propvl-phenvl-methyl polysiloxane for the chromatographic column of filler；Internal diameter is 0.20~0.53mm,
25~75m of column length, 1.12~3 μm of film thickness；
Column temperature: 35~45 DEG C；
Carrier gas: nitrogen；
Flow velocity: 2.5~3.5ml/min；
Detector: FID；
Injector temperature: 120~180 DEG C；
Split ratio: 20:1~30:1；
240 DEG C~280 DEG C of detector temperature；
Head space condition: 75 DEG C~85 DEG C of head space equilibrium temperature；
Head space equilibration time: 25~35min；
Temperature program: being warming up to 100 DEG C after 40 DEG C of 6~10min of holding with 10~20 DEG C/min, keeps after 1~3min again with 20
~40 DEG C/min heating DEG C, keeps 1~3min after being warming up to 180 DEG C；Finally 240 DEG C are risen to 30 DEG C/min, maintain 7~
9min；
C. gas chromatograph detection is carried out to blank solvent, system suitability solution, reference substance solution, test solution.
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| CN111735884A (en) * | 2020-08-04 | 2020-10-02 | 精晶药业股份有限公司 | High performance gas chromatography detection method for triethylamine content in feed liquid |
| CN112379019A (en) * | 2020-11-06 | 2021-02-19 | 郑州原理生物科技有限公司 | Method for detecting residual solvent diethylamine in lidocaine hydrochloride |
| CN112903866A (en) * | 2021-02-02 | 2021-06-04 | 郑州泰丰制药有限公司 | Method for determining triethylamine content in propane fumarate tenofovir |
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