CN108318615A - The method that headspace gas chromatography detects residual solvent in heparin sodium - Google Patents
The method that headspace gas chromatography detects residual solvent in heparin sodium Download PDFInfo
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- CN108318615A CN108318615A CN201810220426.6A CN201810220426A CN108318615A CN 108318615 A CN108318615 A CN 108318615A CN 201810220426 A CN201810220426 A CN 201810220426A CN 108318615 A CN108318615 A CN 108318615A
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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
- G01N30/26—Conditioning of the fluid carrier; Flow patterns
- G01N30/28—Control of physical parameters of the fluid carrier
- G01N30/30—Control of physical parameters of the fluid carrier of temperature
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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
- G01N2030/8872—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 impurities
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Abstract
The present invention relates to drug solvent residue detection technical fields, concretely relate to a kind of method that headspace gas chromatography detects residual solvent in heparin sodium.This method uses headspace gas chromatography, the technical problem of system suitability difference existing for detection method for residual solvent in the heparin sodium of the prior art, impact analysis object and the important parameter headspace sampling balance temperature of internal standard peak area ratio are optimized, head space equilibrium temperature is optimized for 78~82 DEG C by 90 DEG C.The method of residual solvent in headspace gas chromatography detection heparin sodium provided by the invention, analyte and the relative standard deviation of internal standard peak area ratio are respectively less than 1.0% when reference substance being made to repeat sample introduction, and system suitability meets the requirements；This method has many advantages, such as that specificity is good, each analyte separating degree is high, reproducible, high sensitivity simultaneously, the detection limit respectively 0.0008%, 0.0002%, 0.0001% of methanol, ethyl alcohol, acetone, quantitative limit is respectively 0.0023%, 0.0007%, 0.0003%.
Description
Technical field
The present invention relates to drug solvent residue detection technical fields, concretely relate to a kind of headspace gas chromatography inspection
The method for surveying residual solvent in heparin sodium.
Background technology
Heparin sodium is mucopolysaccharide sulfuric acid ester anticoagulant.Heparin sodium is the sulfate of ammoniac by being extracted in the intestinal mucosa of pig or ox
The sodium salt of base glucan belongs to mucopolysaccharide substance.Recent study proves that heparin sodium also has effect for reducing blood fat.Heparin is in the world
The most complicated compound of hitherto known molecular structure, in a short time can not artificial chemistry synthesis, at present only derive from pig
The heparin of mucous membrane of small intestine can be used in clinical treatment.The raw material of heparin bulk pharmaceutical chemicals is heparin crude product, and extraction can only be originated from health
The mucous membrane of small intestine of live pig need to pass through physics and chemistry carries due to containing a large amount of impurities the impurity such as albumen, contaminant nucleic acid, microorganism
Separation process is taken, orientation obtains the complete heparin of natural structure group, to which heparin bulk pharmaceutical chemicals be made.
In the prior art, heparin sodium mostly uses the refined technique of enzymolysis and extraction-resin adsorption-, and subtractive process removes heparin
Various impurity in sodium crude product, obtain refined heparin sodium.Needed in subtractive process with organic solvent such as methanol, ethyl alcohol, acetone etc. into
Row precipitation is separated by solid-liquid separation with realizing, the organic solvent residual in heparin sodium is one of the important indicator required in pharmacopeia, pharmacopeia rule
Fixed, methanol residual, which must not exceed 0.3%, ethyl alcohol residual and must not exceed 0.5%, acetone residue, in heparin sodium must not exceed 0.5%.
The detection method of the prior art (2015 editions《Chinese Pharmacopoeia》Recording method) use the progress internal standard method detection of internal standard compound normal propyl alcohol, inspection
The impurity of survey further includes methanol and acetone in addition to ethyl alcohol.But medicine Qu Fangfa is during atual detection, and system suitability is poor.
Dissolvent residual (official method) system suitability result (90 DEG C of head space equilibrium temperature)
As seen from the experiment, 3 independent experiments repeat in sample introduction, acetone and internal standard peak area ratio repeatability RSD values
Higher and can exceed specified value 5%, method system applicability is undesirable.
Invention content
The present invention provides in a kind of headspace gas chromatography detection heparin sodium to overcome the above-mentioned deficiency of the prior art
The method of residual solvent, it is flat that present invention optimizes important examination parameter-headspace samplings of impact analysis object and internal standard peak area ratio
Weigh temperature, to overcome the technical problem of existing detection method system suitability difference, analyte when reference substance being made to repeat sample introduction
It is respectively less than 1.0% with the relative standard deviation of internal standard peak area ratio, system suitability meets the requirements.
To achieve the goals above, the present invention is achieved by the following technical solutions：
The present invention provides a kind of headspace gas chromatography detect heparin sodium in residual solvent method, this method include with
Lower step：
(1) solution is prepared：Normal propyl alcohol is dissolved in water and is made into inner mark solution, then prepares test solution, mixing respectively
Reference substance storing solution, mixed reference substance solution；
(2) vapor detection：Solvent is measured using headspace injection method, testing conditions and parameter are as follows：
Carrier gas：Nitrogen；
Chromatographic column：DB-624 capillary chromatographic columns；
Detector：Flame ionization ditector (FID)；
Column flow：2.0ml/min；
Detector temperature：250℃；
Hydrogen flow rate：35~40ml/min；
Air velocity：300~400ml/min
Column temperature：Initial temperature is 40 DEG C, maintains 4 minutes, rises to 58 DEG C with 3 DEG C of rate per minute, then with per minute 20
DEG C rate rise to 160 DEG C.
Injector temperature：160℃；Split ratio：10:1；
Input mode：Headspace sampling；
Head space condition：Equilibrium temperature：78~82 DEG C, sample introduction needle temperature：85 DEG C, equilibration time：20 minutes, circulation time：
25 minutes.
Further, the solution preparation includes the following steps：
(1) inner mark solution is prepared：Ultra-pure water 150ml is added into 250ml volumetric flasks, then precision weighs 25 μ l of normal propyl alcohol
In (density 0.80g/ml) to the 250ml volumetric flasks, be diluted with water to scale, shake up be configured to 80 μ g/ml normal propyl alcohol it is molten
Liquid；
(2) test solution is prepared：Precision weighs in heparin sodium sample 2.0g to 10ml volumetric flasks, and inner mark solution is added to dissolve
And it is diluted to scale, it shakes up；Precision pipettes solution 3.0ml, is placed in the ml headspace bottle for being previously added sodium chloride 500mg, close
Envelope, is configured to test solution；
(3) mixing reference substance storing solution is prepared：30ml inner mark solutions are added into 100ml volumetric flasks, then precision weighs first
In alcohol 0.4g, absolute ethyl alcohol 0.4g, acetone 0.08g to the 100ml volumetric flasks, it is diluted to scale with inner mark solution, shakes up preparation
At mixing reference substance storing solution；
(4) mixed reference substance solution：Precision pipettes in mixing reference substance storing solution 10ml to 100ml volumetric flasks, uses internal standard
Liquid is diluted to scale, shakes up；Precision pipettes solution 3.0ml, is placed in the ml headspace bottle for being previously added sodium chloride 500mg, close
Envelope, is configured to mixed reference substance solution.
Further, the vapor detection includes the following steps：
(1) it takes 5 mixed reference substance solution samples to carry out gas Chromatographic Determination, records each component in each sample chromatogram figure
Peak area and internal standard compound peak area；
(2) it takes test solution sample to carry out gas Chromatographic Determination, records each component in test solution sample chromatogram figure
Peak area and internal standard compound peak area；
(3) content of each group solvent composition in test sample is calculated by following equation：
In formula：
Wi：The content of component to be measured, % in test sample；
FFor：Component peaks area measurement and internal standard compound peak area ratio to be measured in test solution；
FIt is right：When 5 sample introduction mixed reference substance solutions, each solvent composition peak area measurement value and internal standard compound peak area ratio
Average value；
WIt is right：The weight (g) of each solvent composition in reference substance solution
1000：The dilution volume (ml) of reference substance
WFor：The sample weighting amount (g) of sample heparin sodium sample in test solution
10：The dilution volume (ml) of test sample.
Further, the testing conditions of the vapor detection and parameter are as follows：
Carrier gas：Nitrogen；
Chromatographic column：DB-624 capillary chromatographic columns；
Detector：Flame ionization ditector (FID)；
Column flow：2.0ml/min；
Detector temperature：250℃；
Hydrogen flow rate：35ml/min；
Air velocity：350ml/min
Column temperature：Initial temperature is 40 DEG C, maintains 4 minutes, rises to 58 DEG C with 3 DEG C of rate per minute, then with per minute 20
DEG C rate rise to 160 DEG C.
Injector temperature：160℃；Split ratio：10:1；
Input mode：Headspace sampling；
Head space condition：Equilibrium temperature：80 DEG C, sample introduction needle temperature：85 DEG C, equilibration time：20 minutes, circulation time：25 points
Clock.
Further, in residual solvent methanol, ethyl alcohol and acetone detection limit be respectively 0.0008%, 0.0002%,
0.0001%.
Further, in residual solvent the quantitative limit of methanol, ethyl alcohol and acetone be respectively 0.0023%, 0.0007%,
0.0003%.
The beneficial effects of the present invention are：
(1) compared with prior art, headspace gas chromatography provided by the invention detects the side of residual solvent in heparin sodium
Method optimizes important examination parameter-headspace sampling equilibrium temperature of impact analysis object and internal standard peak area ratio, existing to overcome
The technical problem for having detection method system suitability difference, the phase of analyte and internal standard peak area ratio when reference substance being made to repeat sample introduction
1.0% is respectively less than to standard deviation, system suitability meets the requirements；
(2) experiment shows that detection method specificity of the invention is good, and each analyte separating degree is high, blank solvent, internal standard,
Sample solution equal not interference measurement at each residual solvent retention time；
(3) method high sensitivity of the invention, methanol, ethyl alcohol, acetone detection limit be respectively 0.0008%,
0.0002%, 0.0001%, quantitative limit is respectively 0.0023%, 0.0007%, 0.0003%；When repeating sample introduction, quantitative limit is dense
The RSD values for spending solution peak area are equal<10%, the RSD values of detection limit strength solution peak area are equal<20%, it meets the requirements.
(4) method accuracy of the invention meets the requirements, as seen from the experiment, methanol, ethyl alcohol, acetone 80%,
100%, for the average recovery rate of 120% concentration level in 95~105% ranges, the RSD values of each concentration level rate of recovery are equal<
5%.
(5) when the conditions such as head space equilibrium temperature, column flow rate, initial column temperature, gas chromatographic column fluctuate in a certain range,
Each analyte and the RSD values of internal standard peak area ratio are equal<5.0%；Each analyte separating degree is equal>3.0；Each analyte theory tower
Plate number is equal>5000；Sample detection result and the relative deviation of old terms testing result are equal<5.0%.Therefore the analysis side of the present invention
In parameter a certain range in method when fluctuation, durability meets the requirements.
Description of the drawings
Fig. 1-Fig. 8 is that the specificity of the detection method of the present invention tests gas chromatogram；
Wherein：Fig. 1 is blank solvent chromatogram, and Fig. 2 is normal propyl alcohol reference substance chromatogram, and Fig. 3 is methanol control product chromatography
Figure, Fig. 4 are ethanol control product chromatogram, and Fig. 5 is acetone control product chromatogram, and Fig. 6 is mark-on sample chromatogram figure, and Fig. 7 is mixing
Reference substance chromatogram, Fig. 8 are test sample chromatogram.
Fig. 9-13 is that the system suitability of the detection method of the present invention tests gas chromatogram；
Wherein：Fig. 9 is the chromatogram of mixed reference substance solution 1, and Figure 10 is the chromatogram of mixed reference substance solution 2, Figure 11
For the chromatogram of mixed reference substance solution 3, Figure 12 is the chromatogram of mixed reference substance solution 4, and Figure 13 is mixed reference substance solution 5
Chromatogram.
Figure 14 is the linear graph of the linear and range experiment of the detection method of the present invention；
Wherein Figure 14 a are Line Chart of the methanol in concentration range, and Figure 14 b are Line Chart of the ethyl alcohol in concentration range,
Figure 14 c are Line Chart of the acetone in concentration range.
Specific implementation mode
It shows that example illustrates certain embodiments of the present invention, and should not be construed as the model of the limitation present invention
It encloses.Present disclosure can be improved from material, method and reaction condition simultaneously, all these improvement should all
It falls within the spirit and scope of the present invention.
Embodiment 1：
The present invention provides a kind of headspace gas chromatography detect heparin sodium in residual solvent method, this method include with
Lower step：
1, solution is prepared
(1) inner mark solution is prepared：Ultra-pure water 150ml is added into 250ml volumetric flasks, then precision weighs 25 μ l of normal propyl alcohol
In (density 0.80g/ml) to the 250ml volumetric flasks, be diluted with water to scale, shake up be configured to 80 μ g/ml normal propyl alcohol it is molten
Liquid；
(2) test solution is prepared：Precision weighs in heparin sodium sample 2.0g to 10ml volumetric flasks, and inner mark solution is added to dissolve
And it is diluted to scale, it shakes up；Precision pipettes solution 3.0ml, is placed in the ml headspace bottle for being previously added sodium chloride 500mg, close
Envelope, is configured to test solution；It repeats to prepare 2 parts, as test solution 1, test solution 2.
(3) mixing reference substance storing solution is prepared：30ml inner mark solutions are added into 100ml volumetric flasks, then precision weighs first
In alcohol 0.4g, absolute ethyl alcohol 0.4g, acetone 0.08g to the 100ml volumetric flasks, it is diluted to scale with inner mark solution, shakes up preparation
At mixing reference substance storing solution；
(4) mixed reference substance solution：Precision pipettes in mixing reference substance storing solution 10ml to 100ml volumetric flasks, uses internal standard
Liquid is diluted to scale, shakes up；Precision pipettes solution 3.0ml, is placed in the ml headspace bottle for being previously added sodium chloride 500mg, close
Envelope, is configured to mixed reference substance solution；It repeats to prepare 6 parts of Duplicate Samples.
2, vapor detection
(1) solvent is measured using headspace injection method, testing conditions and parameter are as follows：
Carrier gas：Nitrogen；
Chromatographic column：DB-624 capillary chromatographic columns (1.80 μm of the μ ms of 30m × 320)；
Detector：Flame ionization ditector (FID)；
Column flow：2.0ml/min；
Detector temperature：250℃；
Hydrogen flow rate：35ml/min；
Air velocity：350ml/min
Column temperature：Initial temperature is 40 DEG C, maintains 4 minutes, rises to 58 DEG C with 3 DEG C of rate per minute, then with per minute 20
DEG C rate rise to 160 DEG C.
Injector temperature：160℃；Split ratio：10:1；
Input mode：Headspace sampling；
Head space condition：Equilibrium temperature：80 DEG C, sample introduction needle temperature：85 DEG C, equilibration time：20 minutes, circulation time：25 points
Clock.
(2) gas phase detection method
1. 5 mixed reference substance solution samples is taken to carry out gas Chromatographic Determination, each component in each sample chromatogram figure is recorded
Peak area and internal standard compound peak area；
2. test solution sample is taken to carry out gas Chromatographic Determination, each group swarming in test solution sample chromatogram figure is recorded
Area and internal standard compound peak area；
3. calculating the content of each group solvent composition in test sample by following equation：
In formula：
Wi：The content of component to be measured, % in test sample；
FFor：Component peaks area measurement and internal standard compound peak area ratio to be measured in test solution；
FIt is right：When 5 sample introduction mixed reference substance solutions, each solvent composition peak area measurement value and internal standard compound peak area ratio
Average value；
WIt is right：The weight (g) of each solvent composition in reference substance solution
1000：The dilution volume (ml) of reference substance
WFor：The sample weighting amount (g) of sample heparin sodium sample in test solution
10：The dilution volume (ml) of test sample.
Embodiment 2：Specificity is tested
1, solution is prepared
Blank solution：Precision measures water 3.0ml, sets and is previously added in the ml headspace bottle of sodium chloride 500mg, seals.
Inner mark solution is prepared：Ultra-pure water 150ml is added into 250ml volumetric flasks, then to weigh 25 μ l of normal propyl alcohol (close for precision
Spend 0.80g/ml) in the 250ml volumetric flasks, it is diluted with water to scale, shakes up the normal propyl alcohol solution for being configured to 80 μ g/ml；
Normal propyl alcohol reference substance solution：Precision measures inner mark solution 3.0ml, sets the head space for being previously added sodium chloride 500mg
In bottle, sealing.
Methanol control product solution：Precision weighs methanol 0.04g, sets in the 100ml volumetric flasks there are about 30ml water, is diluted with water
It to scale, shakes up, takes solution 3.0ml, set and be previously added in the ml headspace bottle of sodium chloride 500mg, seal.
Ethanol control product solution：Precision weighs ethyl alcohol 0.04g, sets in the 100ml volumetric flasks there are about 30ml water, is diluted with water
It to scale, shakes up, takes solution 3.0ml, set and be previously added in the ml headspace bottle of sodium chloride 500mg, seal.
Acetone control product solution：Precision weighs acetone 0.08g, sets in the 100ml volumetric flasks there are about 30ml water, is diluted with water
It to scale, shakes up, precision pipettes solution 1.0ml, sets in 10ml volumetric flasks, is diluted with water to scale, shakes up.Take the solution
3.0ml sets and is previously added in the ml headspace bottle of sodium chloride 500mg, sealing.
Mixed reference substance solution：Precision pipettes mixing reference substance storing solution 10ml, sets in 100ml volumetric flasks, uses internal standard solution
It is diluted to scale, is shaken up.Precision pipettes above-mentioned solution 3.0ml, sets and is previously added in the ml headspace bottle of sodium chloride 500mg.
Test solution：Precision weighs test sample 2.0g, sets in 10ml volumetric flasks, adds inner mark solution to dissolve and is diluted to quarter
Degree, shakes up.Precision pipettes above-mentioned solution 3.0ml, sets and is previously added in the ml headspace bottle of sodium chloride 500mg, sealing.
Mark-on sample solution：Precision weighs test sample 2.0g, sets in 10ml volumetric flasks, while mixing reference substance deposit is added
Solution 1ml adds inner mark solution to dissolve and is diluted to scale, shakes up.Precision pipettes above-mentioned solution 3.0ml, sets and has been previously added chlorine
In the ml headspace bottle for changing sodium 500mg, sealing.
2, operating procedure
Taking above-mentioned sample solution, sample introduction is analyzed, records chromatogram, and test result is shown in Table 1, and experiment collection of illustrative plates is shown in shown in Fig. 1-8.
1 dissolvent residual specificity test result of table
As seen from the experiment, each analyte separation is good, and blank solvent, internal standard, sample solution are protected in each residual solvent
Stay at the time that interference measurement, method specificity be not good.
Embodiment 3：System suitability is tested
Preceding 5 parts of mixing reference substance Duplicate Samples in Example 1, each one needle of Duplicate Samples sample introduction carry out vapor detection, note
Chromatogram is recorded, chromatogram is as described and depicted in figs. 9-13.The data reflected in chromatogram are subjected to finishing analysis, system suitability knot
Fruit analysis result is as shown in table 1.
2 dissolvent residual system suitability result of table (80 DEG C of head space equilibrium temperature)
As seen from the experiment, each analyte detaches well under the established GC conditions of technical solution of the present invention,
Column effect meets regulation, and each analyte peak area ratio repeatability RSD values are respectively less than 5.0%, and method system applicability meets the requirements.
Embodiment 4：Detection limit, quantitative limit experiment
1, solution is prepared
Blank solution：Precision measures inner mark solution 3.0ml, sets and is previously added in the ml headspace bottle of sodium chloride 500mg, close
Envelope.
Methanol stock solution：Precision weighs methanol 0.4g, sets in the 100ml volumetric flasks there are about 30ml inner mark solutions, adds interior
Mark solution is diluted to scale, shakes up.
Ethyl alcohol stock solution：Precision weighs ethyl alcohol 0.4g, sets in the 100ml volumetric flasks there are about 30ml inner mark solutions, adds interior
Mark solution is diluted to scale, shakes up.
Acetone stock solution：Precision weighs acetone 0.08g, sets in the 100ml volumetric flasks there are about 30ml inner mark solutions, adds interior
Mark solution is diluted to scale, shakes up.
2, test method
It takes methanol, ethyl alcohol, acetone stock solution appropriate respectively, is gradually diluted with inner mark solution and sample introduction is analyzed, work as analysis
Solution concentration of the object peak signal-to-noise ratio in 8~12 range is the quantitative limit of the analyte, when analyte peak signal-to-noise ratio is 2~4
Solution concentration when range is the detection limit of the analyte.
Signal-to-noise ratio (S/N) is calculated with chromatographic software as the following formula：
In formula：Methanol, ethyl alcohol or acetone peak height in H-quantitative limit or detection limit solution collection of illustrative plates；
(period is no less than first in quantitative limit or detection limit solution near peak position to be measured in h-blank solution collection of illustrative plates
5 times of half-peak breadths of alcohol, ethyl alcohol or acetone peak) baseline noise
It takes above-mentioned quantitative limit concentration to repeat sample introduction 6 times with detection limit concentration samples, records chromatogram, test result is shown in Table 3
With table 4.
3 quantitative limit test result of table
The detection limit test result of table 4
As seen from the experiment：Methanol, ethyl alcohol and acetone detection limit be respectively 0.0008%, 0.0002%,
0.0001%, quantitative limit is respectively 0.0023%, 0.0007%, 0.0003%, and method is sensitive；When repeating sample introduction, quantitative limit is dense
The RSD values for spending solution peak area are equal<10%, the RSD values of detection limit strength solution peak area are equal<20%, it meets the requirements.
Embodiment 4：The experiment of linear and range
1, solution is prepared
Quantitative limit concentration level solution：Precision pipette mixing reference substance storing solution it is appropriate, step by step plus inner mark solution dilution, shake
It is even so that methanol, ethyl alcohol, acetone concentration are quantitative limit concentration.Precision pipettes above-mentioned solution 3.0ml, sets and has been previously added chlorination
In the ml headspace bottle of sodium 500mg, sealing prepares 2 parts of parallel samples.
20% concentration level solution：Precision pipettes mixing reference substance storing solution 0.20ml, sets in 10ml volumetric flasks, adds internal standard
Solution is diluted to scale, shakes up.Precision pipettes above-mentioned solution 3.0ml, sets and is previously added in the ml headspace bottle of sodium chloride 500mg,
Sealing prepares 2 parts of parallel samples.
50% concentration level solution：Precision pipettes mixing reference substance storing solution 0.50ml, sets in 10ml volumetric flasks, adds internal standard
Solution is diluted to scale, shakes up.Precision pipettes above-mentioned solution 3.0ml, sets and is previously added in the ml headspace bottle of sodium chloride 500mg,
Sealing prepares 2 parts of parallel samples.
80% concentration level solution：Precision pipettes mixing reference substance storing solution 0.80ml, sets in 10ml volumetric flasks, adds internal standard
Solution is diluted to scale, shakes up.Precision pipettes above-mentioned solution 3.0ml, sets and is previously added in the ml headspace bottle of sodium chloride 500mg,
Sealing prepares 2 parts of parallel samples.
100% concentration level solution：Precision pipettes mixing reference substance storing solution 1.0ml, sets in 10ml volumetric flasks, adds internal standard
Solution is diluted to scale, shakes up.Precision pipettes above-mentioned solution 3.0ml, sets and is previously added in the ml headspace bottle of sodium chloride 500mg,
Sealing prepares 2 parts of parallel samples.
200% concentration level solution：Precision pipettes mixing reference substance storing solution 2.0ml, sets in 10ml volumetric flasks, adds internal standard
Solution is diluted to scale, shakes up.Precision pipettes above-mentioned solution 3.0ml, sets and is previously added in the ml headspace bottle of sodium chloride 500mg,
Sealing prepares 2 parts of parallel samples.
300% concentration level solution：Precision pipettes mixing reference substance storing solution 3.0ml, sets in 10ml volumetric flasks, adds internal standard
Solution is diluted to scale, shakes up.Precision pipettes above-mentioned solution 3.0ml, sets and is previously added in the ml headspace bottle of sodium chloride 500mg,
Sealing prepares 2 parts of parallel samples.
2, test method
Taking above-mentioned sample solution, sample introduction is analyzed, and each Duplicate Samples record chromatogram, with concentration (x) to analyte into 1 needle
Linear regression is carried out with internal standard compound peak area ratio (y), linear test the results are shown in Table 5, table 6 and table 7, Line Chart such as Figure 14.
5 methanol linearity and range of table investigates result
6 ethyl alcohol linearity and range of table investigates result
7 acetone linearity and range of table investigates result
As seen from the experiment, methanol exists in 4.53~1061.1 μ g/ml, ethyl alcohol in 1.48~1108.8 μ g/ml, acetone
Linear coefficient R in 0.60~22.62 μ g/ml concentration ranges2It is all higher than 0.995, linear relationship is good.
Embodiment 5：Experiment is investigated in accuracy
1, solution is prepared
Methanol stock solution：Precision weighs methanol 0.4g, sets in the 100ml volumetric flasks there are about 30ml inner mark solutions, adds interior
Mark solution is diluted to scale, shakes up.
Ethyl alcohol stock solution：Precision weighs ethyl alcohol 0.4g, sets in the 100ml volumetric flasks there are about 30ml inner mark solutions, adds interior
Mark solution is diluted to scale, shakes up.
Acetone stock solution：Precision weighs acetone about 0.08g, sets in the 100ml volumetric flasks there are about 30ml inner mark solutions, adds
Inner mark solution is diluted to scale, shakes up.
Test solution：Precision weighs test sample 2.0g, sets in 10ml volumetric flasks, adds inner mark solution to dissolve and is diluted to quarter
Degree, shakes up.Precision pipettes above-mentioned solution 3.0ml, sets and is previously added in the ml headspace bottle of sodium chloride 500mg, sealing, repeats to prepare
3 parts.
Reference substance solution：Precision weighs methanol 0.4g, absolute ethyl alcohol 0.4g, acetone 0.08g, sets that there are about 30ml internal standards are molten
In the 100ml volumetric flasks of liquid, adding internal standard solution to be diluted to scale, shake up, precision pipettes solution 10ml, sets in 100ml volumetric flasks,
It is diluted to scale with internal standard solution, is shaken up.Precision pipettes above-mentioned solution 3.0ml, sets the ml headspace bottle for being previously added sodium chloride 500mg
In.
80% concentration level solution：Precision weighs test sample 2.0g, sets in 10ml volumetric flasks, adds methanol stock solution
0.8ml, ethyl alcohol stock solution 2.0ml, acetone stock solution 0.8ml, dissolve and are diluted to inner mark solution scale, shake up.Essence
It is close to pipette above-mentioned solution 3.0ml, it sets and is previously added in the ml headspace bottle of sodium chloride 500mg, seal, prepare 3 parts of parallel sample.
100% concentration level solution：Precision weighs test sample 2.0g, sets in 10ml volumetric flasks, adds methanol stock solution
1.0ml, ethyl alcohol stock solution 2.5ml, acetone stock solution 1.0ml, dissolve and are diluted to inner mark solution scale, shake up.Essence
It is close to pipette above-mentioned solution 3.0ml, it sets and is previously added in the ml headspace bottle of sodium chloride 500mg, seal, prepare 3 parts of parallel sample.
120% concentration level solution：Precision weighs test sample 2.0g, sets in 10ml volumetric flasks, adds methanol stock solution
1.2ml, ethyl alcohol stock solution 3.0ml, acetone stock solution 1.2ml, dissolve and are diluted to inner mark solution scale, shake up.Essence
It is close to pipette above-mentioned solution 3.0ml, it sets and is previously added in the ml headspace bottle of sodium chloride 500mg, seal, prepare 3 parts of parallel sample.
2, test method
Taking above-mentioned sample solution, sample introduction is analyzed, and each Duplicate Samples record chromatogram into 1 needle, calculate methanol, ethyl alcohol, acetone
In the rate of recovery of each concentration level, test result is shown in Table 8.
Result is investigated in 8 accuracy of table
As seen from the experiment, methanol, ethyl alcohol, acetone exist in the average recovery rate of 80%, 100%, 120% concentration level
In 95~105% ranges, the RSD values of each concentration level rate of recovery are equal<5%, method accuracy meets the requirements.
Embodiment 6：Precision investigates experiment
1, solution is prepared
Sample solution：Test sample about 2.0g is taken, it is accurately weighed, it sets in 10ml volumetric flasks, inner mark solution is added to dissolve and dilute
To scale, shake up.Precision pipettes above-mentioned solution 3.0ml, sets and is previously added in the ml headspace bottle of sodium chloride 500mg, sealing.Weight
It replicates 6 parts standby.
Reference substance solution：Precision pipettes reference substance stock solution 10ml, sets in 100ml volumetric flasks, is diluted to internal standard solution
Scale shakes up.Precision pipettes above-mentioned solution 3.0ml, sets and is previously added in the ml headspace bottle of sodium chloride 500mg, prepares 6 parts and puts down
Row sample.
2, test method
Sample is being prepared as stated above on the same day by same analysis personnel, investigates repeatability.Existed by different analysis personnel
Same laboratory does not prepare sample as stated above on the same day, investigates Intermediate precision.Precision test result is shown in Table 9.
9 precision of table investigates result
As seen from the experiment, the RSD values of same analysis personnel repeatability measurement result are that 3.8%, 0%, RSD values are equal<
5%, repeatability meets the requirements；The RSD values of different analysis personnel Intermediate precision measurement results are 1.5%, RSD values<5%, in
Between precision meet the requirements.
Embodiment 7：Durability investigates experiment
1, solution is prepared
Reference substance solution：Precision pipettes the reference substance stock solution 10ml in embodiment 1, sets in 100ml volumetric flasks, with interior
Standard liquid is diluted to scale, shakes up.Precision pipettes above-mentioned solution 3.0ml, sets and is previously added in the ml headspace bottle of sodium chloride 500mg,
Sealing.
Sample solution：Precision weighs test sample 2.0g, sets in 10ml volumetric flasks, adds inner mark solution to dissolve and is diluted to quarter
Degree, shakes up.Precision pipettes above-mentioned solution 3.0ml, sets and is previously added in the ml headspace bottle of sodium chloride 500mg, sealing.
2, test method
When the conditions such as head space equilibrium temperature, column flow rate, initial column temperature, gas chromatographic column fluctuate in a certain range, examine
Each analyte peak area ratio, the situation of change of separating degree and theoretical cam curve, sample detection result are examined, it is specific to investigate condition such as
Shown in lower：
Old terms：Chromatographic column is DB-624 capillary columns (1.80 μm of the μ ms of 30m × 320)；Detector is FID detectors；
Input mode is headspace sampling；Head space equilibrium temperature is 80 DEG C, and headspace sampling needle temperature is 85 DEG C, and head space equilibration time is 20 points
Clock, head space circulation time are 25 minutes；Initial temperature is 40 DEG C, is kept for 4 minutes, and heating rate is 3 DEG C/min, rises to 58 DEG C,
Again 160 DEG C are risen to 20 DEG C/min rates；Injector temperature is 160 DEG C；Detector temperature is 250 DEG C；Column flow rate is 2.0ml/
min；Split ratio is 10:1；Sampling volume is 1.0ml.
Condition 1：38 DEG C of initial column temperature, other same old terms.
Condition 2：42 DEG C of initial column temperature, other same old terms.
Condition 3：Column flow rate is 1.8ml/min, other same old terms.
Condition 4：Column flow rate is 2.2ml/min, other same old terms.
Condition 5：Head space equilibrium temperature is 75 DEG C, other same old terms.
Condition 6：Head space equilibrium temperature is 85 DEG C, other same old terms.
Condition 7：Gas chromatographic column is different lot numbers, other same old terms.
The sample solution in step 1 is taken, is analyzed at different conditions, chromatogram is recorded, peak area ratio is investigated, divides
From degree, the relative deviation of theoretical cam curve, sample detection result and old terms testing result, test result is shown in Table 10 and table 11.
Peak area ratio, separating degree and theoretical cam curve investigate result under 10 different condition of table
11 sample detection test result of table
Test result shows：When the conditions such as head space equilibrium temperature, column flow rate, initial column temperature, gas chromatographic column are in certain model
When enclosing interior fluctuation, each analyte and the RSD values of internal standard peak area ratio are equal<5.0%；Each analyte separating degree is equal>3.0；Each point
It is equal to analyse object theoretical cam curve>5000；Sample detection result and the relative deviation of old terms testing result are equal<5.0%.To sum up institute
It states, when analysis method fluctuates in a certain range, durability meets the requirements.
Embodiment 8：Solution stability testing
1, solution is prepared
Reference substance solution：Precision pipettes the reference substance stock solution 10ml in embodiment 1, sets in 100ml volumetric flasks, with interior
Standard liquid is diluted to scale, shakes up.Precision pipettes above-mentioned solution 3.0ml, sets and is previously added in the ml headspace bottle of sodium chloride 500mg,
Sealing.
Sample mark-on solution：Test sample about 5.0g is taken, it is accurately weighed, it sets in 25ml volumetric flasks, while reference substance storage is added
Standby solution 2.5ml, adds inner mark solution to dissolve and is diluted to scale, shake up.Precision pipettes above-mentioned solution 3.0ml, sets and is previously added
In the ml headspace bottle for having sodium chloride 500mg, sealing.
2, test method
It is steady to investigate the solution of reference substance solution and sample solution after being placed at room temperature for 0h, 5h, 10h, 15h, 20h, 35h hours
It is qualitative.Taking sample mark-on solution, sample introduction is analyzed, records chromatogram, and test result is shown in Table 12, table 13.
12 reference substance solution study on the stability result of table
13 sample solution study on the stability result of table
Test result shows：Be placed at room temperature for 0h, 3h, 6h, 9h, 12h, for 24 hours after, each time point analyte of reference substance solution with
Internal standard peak area ratio RSD values are equal<2.0%, each time point analyte of mark-on sample and internal standard peak area ratio RSD values are equal<
10.0%.In conclusion sample solution places testing result in for 24 hours, without significant change, stability of solution meets the requirements.
The foregoing is only a preferred embodiment of the present invention, but scope of protection of the present invention is not limited thereto,
Any one skilled in the art in the technical scope disclosed by the present invention, according to the technique and scheme of the present invention and its
Inventive concept is subject to equivalent substitution or change, should be covered by the protection scope of the present invention.
Claims (6)
1. a kind of method of residual solvent in headspace gas chromatography detection heparin sodium, which is characterized in that this method includes following
Step：
(1) solution is prepared：Normal propyl alcohol is dissolved in water and is made into inner mark solution, then prepares test solution, mixing control respectively
Product storing solution, mixed reference substance solution；
(2) vapor detection：Solvent is measured using headspace injection method, testing conditions and parameter are as follows：
Carrier gas：Nitrogen；
Chromatographic column：DB-624 capillary chromatographic columns；
Detector：Flame ionization ditector (FID)；
Column flow：2.0ml/min；
Detector temperature：250℃；
Hydrogen flow rate：35~40ml/min；
Air velocity：300~400ml/min
Column temperature：Initial temperature is 40 DEG C, maintains 4 minutes, rises to 58 DEG C with 3 DEG C of rate per minute, then with 20 DEG C per minute
Rate rises to 160 DEG C.
Injector temperature：160℃；Split ratio：10:1；
Input mode：Headspace sampling；
Head space condition：Equilibrium temperature：78~82 DEG C, sample introduction needle temperature：85 DEG C, equilibration time：20 minutes, circulation time：25 points
Clock.
2. the method for residual solvent, feature in a kind of headspace gas chromatography detection heparin sodium according to claim 1
It is, the solution preparation includes the following steps：
(1) inner mark solution is prepared：Ultra-pure water 150ml is added into 250ml volumetric flasks, then precision weighs 25 μ l (density of normal propyl alcohol
0.80g/ml) in the 250ml volumetric flasks, it is diluted with water to scale, shakes up the normal propyl alcohol solution for being configured to 80 μ g/ml；
(2) test solution is prepared：Precision weighs in heparin sodium sample 2.0g to 10ml volumetric flasks, add inner mark solution dissolve and it is dilute
It releases to scale, shakes up；Precision pipettes solution 3.0ml, is placed in the ml headspace bottle for being previously added sodium chloride 500mg, and sealing is matched
Test solution is made；
(3) mixing reference substance storing solution is prepared：30ml inner mark solutions are added into 100ml volumetric flasks, then precision weighs methanol
In 0.4g, absolute ethyl alcohol 0.4g, acetone 0.08g to the 100ml volumetric flasks, it is diluted to scale with inner mark solution, shakes up and is configured to
Mix reference substance storing solution；
(4) mixed reference substance solution：Precision pipettes in mixing reference substance storing solution 10ml to 100ml volumetric flasks, dilute with internal standard solution
It releases to scale, shakes up；Precision pipettes solution 3.0ml, is placed in the ml headspace bottle for being previously added sodium chloride 500mg, and sealing is matched
Mixed reference substance solution is made.
3. the method for residual solvent, feature in a kind of headspace gas chromatography detection heparin sodium according to claim 1
It is, the vapor detection includes the following steps：
(1) it takes 5 mixed reference substance solution samples to carry out gas Chromatographic Determination, records each group swarming face in each sample chromatogram figure
Product and internal standard compound peak area；
(2) it takes test solution sample to carry out gas Chromatographic Determination, records each group swarming face in test solution sample chromatogram figure
Product and internal standard compound peak area；
(3) content of each group solvent composition in test sample is calculated by following equation：
In formula：
Wi：The content of component to be measured, % in test sample；
FFor：Component peaks area measurement and internal standard compound peak area ratio to be measured in test solution；
FIt is right：When 5 sample introduction mixed reference substance solutions, each solvent composition peak area measurement value is averaged with internal standard compound peak area ratio
Value；
WIt is right：The weight (g) of each solvent composition in reference substance solution
1000：The dilution volume (ml) of reference substance
WFor：The sample weighting amount (g) of sample heparin sodium sample in test solution
10：The dilution volume (ml) of test sample.
4. the method for residual solvent, feature in a kind of headspace gas chromatography detection heparin sodium according to claim 1
It is, the testing conditions and parameter of the vapor detection are as follows：
Carrier gas：Nitrogen；
Chromatographic column：DB-624 capillary chromatographic columns；
Detector：Flame ionization ditector (FID)；
Column flow：2.0ml/min；
Detector temperature：250℃；
Hydrogen flow rate：35ml/min；
Air velocity：350ml/min
Column temperature：Initial temperature is 40 DEG C, maintains 4 minutes, rises to 58 DEG C with 3 DEG C of rate per minute, then with 20 DEG C per minute
Rate rises to 160 DEG C.
Injector temperature：160℃；Split ratio：10:1；
Input mode：Headspace sampling；
Head space condition：Equilibrium temperature：80 DEG C, sample introduction needle temperature：85 DEG C, equilibration time：20 minutes, circulation time：25 minutes.
5. the method for residual solvent, feature in a kind of headspace gas chromatography detection heparin sodium according to claim 1
It is, the detection limit of methanol, ethyl alcohol and acetone is respectively 0.0008%, 0.0002%, 0.0001% in residual solvent.
6. the method for residual solvent, feature in a kind of headspace gas chromatography detection heparin sodium according to claim 1
It is, the quantitative limit of methanol, ethyl alcohol and acetone is respectively 0.0023%, 0.0007%, 0.0003% in residual solvent.
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| CN111044629A (en) * | 2019-12-24 | 2020-04-21 | 湖北亿诺瑞生物制药有限公司 | Method for analyzing residual benzyl chloride in enoxaparin sodium |
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