CN110196304A - A method of detection Vardenafil hydrochloric acid organic solvent residual in raw medicine amount - Google Patents
A method of detection Vardenafil hydrochloric acid organic solvent residual in raw medicine amount Download PDFInfo
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- G—PHYSICS
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- 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
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Abstract
The invention belongs to pharmaceutical technology fields, more particularly to a kind of method for detecting Vardenafil hydrochloric acid organic solvent residual in raw medicine, the method for especially detecting 3 kinds of acetone in Vardenafil hydrochloric acid, tetrahydrofuran and methylene chloride organic solvent residual contents simultaneously with head space capillary gas chromatography.Method provided by the invention has the features such as easy to operate, high sensitivity, specificity is strong, reproducible, and accuracy is high, can be used for the quality control of Vardenafil hydrochloric acid bulk pharmaceutical chemicals.
Description
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to organic solvent is residual in a kind of detection Vardenafil hydrochloric acid bulk pharmaceutical chemicals
The method stayed especially detects acetone in Vardenafil hydrochloric acid, tetrahydrofuran, dichloro with headspace capillary GC simultaneously
The method of 3 kinds of organic solvent residual contents of methane.
Background technique
Erectile dysfunction (Erectile Dysfunction, ED), is commonly called as " impotence ", refers to that man under sexual stimulus, holds
Continuous ground cannot reach or maintain the telotism of enough hardness to complete to be satisfied with sexual life, and the course of disease can be clinical at 3 months or more
Diagnose ED.According to epidemic data (J Androl, 2011,32:496), the ED totality illness rate of China's adult male is
17.1%, and increased with the increase at age, crowd reaches 29.1% within 50 years old or more.Calculate according to gross data, China male
ED patient about 100,000,000 people, it is close with the disease incidence of diabetes, with the hair of China's hypertension, diabetes and obesity syndrome
Sick rate rises, and the ED case thus caused also will persistently rise, and ED has become one of the important diseases of puzzlement male.
" European Urology Association male sexual disfunction practice guidelines (version in 2013) ", " Japanese ED diagnosis and treatment guide
(version in 2008) " and by branch, andrology, Chinese Medical Association in 2004 publication " male erectile dysfunction diagnosis and treatment guide " in
PDE5 inhibitor is classified as to the first-line drug of ED treatment.Mainstream medicine is silaenafil (Viagra, the Wan Ai of Pfizer at present
Can), gift come tadalafil (Cialis, Xi Aili) and Bayer Vardenafil (Levitra, Ai Lida).These three drugs
Substantially similar in terms of pharmacotoxicological effect, all it is that cGMP is raised by selective depression PDE5, promotes one under sexual stimulus effect
Nitrogen oxide (NO) release makes penis vessel smooth muscle relaxation, and cavernosa blood flow increases, blood sinus is congested, to promote to erect.
Vardenafil hydrochloric acid (Vardenafil) is the potent, Gao Xuan of a new generation developed by Bayer and Ge Lansu Shi Ke company
Selecting property PDE5 inhibitor is the oral medicine of the 3rd treatment ED after silaenafil, Tadalafei.With first generation silaenafil
It compares, Vardenafil is optimized on molecular structure, has small dosage, rapid-action, persistent, tolerance good, secondary
Many advantages, such as small is acted on, is the most fast PDE5 inhibitor (can work in 10min) that works found so far.It is a large amount of clinical
Studies have shown that it has significant curative effect to the ED patient of the various causes of disease, various degree, various age brackets, in particular for refractory
Property ED and diabetic keratopathy ED.Meanwhile Vardenafil is also that the whole world is first clinical using quantizating index (erection duration) progress
The PDE5 inhibitor of research, it was demonstrated that it can safely, effectively extend holds with or without the erection of underlying disease ED patient
The continuous time.
Pharmacopoeia of each country is required to carry out residual solvent inspection to bulk pharmaceutical chemicals, to control organic solvent used in production process
Or residual quantity of the volatile impurity in bulk pharmaceutical chemicals, to guarantee drug safety.The present invention is directed to the synthesis system of Vardenafil hydrochloric acid
Using in standby technique and reacting the organic solvent generated has acetone, tetrahydrofuran, methylene chloride and n,N-Dimethylformamide, by
It is smaller and soluble easily in water in n,N-Dimethylformamide usage amount, it can be completely removed in subsequent water washing operations several times.Therefore
Acetone, 3 kinds of tetrahydrofuran, methylene chloride organic solvent residuals introduced for synthesis technology, utilizes head space capillary gas phase color
Spectrometry, and the content for detecting this 3 kinds of organic solvent residuals simultaneously under suitable chromatographic condition is selected, preferably in control product
In quality.
Summary of the invention
The present invention is directed to solve at least some of the technical problems in related technologies.The present inventor
Think that 3 kinds of remaining acetone in Vardenafil hydrochloric acid, tetrahydrofuran, methylene chloride organic solvents will affect Drug safety,
Therefore, it is necessary to detect to 3 kinds of acetone therein, tetrahydrofuran, methylene chloride organic solvent residuals.
The technical problem to be solved by the invention is to provide a kind of sides of organic solvent residual in detection Vardenafil hydrochloric acid
Method, fast and accurately feature easy using gas chromatography, while detect the acetone in Vardenafil hydrochloric acid, tetrahydrofuran,
3 kinds of Determination of Residual Organic Solvents of methylene chloride.It is common low boiling point organic solvent in view of acetone, tetrahydrofuran, methylene chloride, examines
Consider Vardenafil hydrochloric acid trihydrate to dissolve in 5% phosphoric acid solution, while 5% phosphoric acid solution and these three residuals are organic molten
Agent difference is more apparent, therefore selects 5% phosphoric acid solution as sample preparation solvent.
According to domestic Extra Pharmacopoeia Martindale and the relevant technologies guideline relevant regulations and requirement, since these three solvent boiling points are not high
And polarity difference is smaller, referring to the gas phase detection method of common solvent, capillary column headspace injection method is selected to carry out method screening,
Separating degree test result shows that the separating degree of each solvent is good, has primarily determined the chromatostrip of this product residual solvent detection method
Part.It is studied subsequently through detailed methodology validation, the results showed that each investigation project of each residual solvent is equal under the chromatographic condition
It meets the requirements.
The present invention solves above-mentioned technical problem by following technical proposal.
The method of organic solvent residual, is detected simultaneously with head space capillary gas chromatography in a kind of detection Vardenafil hydrochloric acid
3 kinds of acetone, tetrahydrofuran and methylene chloride Determination of Residual Organic Solvents, step in Vardenafil hydrochloric acid specifically:
Chromatographic condition: taking polyethylene glycol (or polarity is close) as the capillary chromatographic column of fixer；Column temperature is 40 DEG C, is maintained
10min, injector temperature are 210 DEG C, and using flame ionization ditector (FID), detector temperature is 250 DEG C；Carrier gas is
Nitrogen, flow velocity 3.5ml/min；Ml headspace bottle equilibrium temperature is 80 DEG C, equilibration time 35min, split ratio 20:1.
The preparation of reference substance solution: precision measurement acetone, tetrahydrofuran and methylene chloride are each appropriate, with 5% phosphoric acid solution
The mixed solution of about respectively 0.25mg containing acetone in every 1ml, 36 μ g of tetrahydrofuran and 30 μ g of methylene chloride is made in quantitative dilution, shakes
It is even to obtain the final product；
The preparation of test solution: precision weighs this product about 1.0g, sets in 20ml measuring bottle, adds the dissolution of 5% phosphoric acid solution simultaneously
It is diluted to scale, shakes up to obtain the final product；
Precision measures above-mentioned reference substance solution 2ml headspace sampling, and the separating degree between each peak should meet the requirements.Another accurate amount
Each 2ml headspace sampling of above-mentioned test solution and control solution is taken, chromatogram is recorded, by external standard method with calculated by peak area.
It, can be effectively to 3 kinds of residual organic solvent contents in Vardenafil hydrochloric acid using method of the present invention
It carries out while detecting.
According to an embodiment of the invention, inventor is by a series of methodological study of following systems to the detection method
Various performances are evaluated:
According to an embodiment of the invention, inventor is tested by the employment and suitability test (E & ST) and specificity of detection method to method
Reliability is evaluated.In employment and suitability test (E & ST), separating degree is most important evaluation index.In embodiment according to the present invention
Experimental result, blank solvent is noiseless to each residual solvent blob detection to be measured, and the peak-to-peak separating degree of adjacent solvent is all larger than
1.5, acetone, tetrahydrofuran, methylene chloride peak area relative standard deviation (RSD) be respectively 3.0%, 4.0%, 8.6%,
Less than 10.0%, it is seen that the dispersion degree very little between measurement result is repeated several times, thus, it can be seen that according to an embodiment of the present invention
Detection method can be with the residual of organic solvent in higher reliability rapid and accurate determination Vardenafil hydrochloric acid bulk pharmaceutical chemicals.
According to an embodiment of the invention, inventor carries out the sensitivity of detection method by detection limit and quantitative limit test
Evaluation.Detection limit and quantitative limit refer to can detect and accurate quantitative analysis test substance in the given degree of reliability from sample
Cmin or minimum according to being the key index of evaluation method sensitivity.Experiment in embodiment according to the present invention
As a result, headspace capillary GC of the invention, the detection of acetone, tetrahydrofuran, methylene chloride, which limits, is respectively equivalent to sample
2.001ppm, 1.627ppm, 2.743ppm of product concentration；Acetone, tetrahydrofuran, methylene chloride quantitative limit be respectively equivalent to sample
7.845ppm, 4.849ppm, 10.619ppm of product concentration.Illustrate that the detection method can be with higher sensitivity quick and precisely
Measure the residual of organic solvent in Vardenafil hydrochloric acid bulk pharmaceutical chemicals.
According to an embodiment of the invention, inventor is commented by the range of linearity of the linear test to the detection method
Valence.Linear regression be using the regression analysis in mathematical statistics, it is complementary fixed between two or more parameter to determine
A kind of one of statistical analysis technique of magnitude relation is simply linear relationship in the correlativity of variable, if at random the most
There are linear relationships between variable and variable, then the point obtained by test data will be dispersed in around a certain straight line.According to
Experimental result in the embodiment of the present invention, acetone, tetrahydrofuran, methylene chloride are in quantitative limit concentration to 120% sample concentration
In range, the coefficient R of concentration and peak area equation of linear regression is all larger than 0.99, the y intercept of each linear equation with
The absolute value of the ratio between response is respectively 1.4%, 0.6%, 4.2%, respectively less than 10.0% when 100% concentration.Fall in the range
Interior acetone, tetrahydrofuran, methylene chloride content can be calculated by corresponding linear equation, thus the detection side
Method can be with the residual of organic solvent in Accurate Determining Vardenafil hydrochloric acid bulk pharmaceutical chemicals.
According to an embodiment of the invention, inventor is commented by precision of the repetitive test to the detection method
Valence.Repetitive test refers to identical method, same test material, between the series of results obtained at identical conditions
Consistent degree.Identical condition refers to same operator, same measuring instrument, same place, identical process of measurement and of short duration
Duplicate measurements in time.Intermediate precision test replacement analysis personnel, analysis date.Experiment in embodiment according to the present invention
As a result, the rate of recovery of acetone, tetrahydrofuran and methylene chloride is equal in 6 parts of same concentrations mark-on test solutions in repetitive test
Between 80.0-120.0%, inventor also detects the precision of the detection method by Intermediate precision test,
As a result RSD is respectively less than 10.0%.Acetone in 12 parts of test solutions, tetrahydrofuran, methylene chloride average recovery rate exist
Between 80.0%-120.0%, RSD is respectively less than 10.0%, and Intermediate precision is good, which can be with higher precision
The residual of organic solvent in property rapid and accurate determination Vardenafil hydrochloric acid bulk pharmaceutical chemicals.
According to an embodiment of the invention, inventor carries out the accuracy of the detection method by sample recovery rate test
Evaluation.Recovery test is that a certain amount of standard substance is added in the sample of detection, tests the standard substance added
The rate of recovery can measure cross contamination, the sample loss, instrument performance of the Matrix effects, sample in pre-treatment or test process
Deng.Experimental result in embodiment according to the present invention, three 9 parts of senior middle school's low concentration within the scope of 80%-120% concentration level
Between 80.0%-120.0%, RSD value is respectively less than the rate of recovery of acetone, tetrahydrofuran and methylene chloride in sample
10.0%, which can quickly measure the residual of organic solvent in Vardenafil hydrochloric acid bulk pharmaceutical chemicals with higher accuracy
It stays.
According to an embodiment of the invention, organic in above-mentioned head space capillary gas chromatography detection Vardenafil hydrochloric acid bulk pharmaceutical chemicals
The method of dissolvent residual has high efficiency, sensitivity, specificity and accuracy, can be to the quality of Vardenafil hydrochloric acid bulk pharmaceutical chemicals
It control effectively.
Specific embodiment
The solution of the present invention is explained below in conjunction with embodiment.It will be understood to those of skill in the art that following
Embodiment is merely to illustrate the present invention, and should not be taken as limiting the scope of the invention.Particular technique or item are not specified in embodiment
Part, it described technology or conditions or is carried out according to the literature in the art according to product description.Agents useful for same or instrument
Production firm person is not specified in device, and being can be with conventional products that are commercially available.
Conventional method: it unless expressly stated, is analyzed in the examples below that using following instruments and condition:
Instrument: Shimadzu GC-2014 gas chromatograph, fid detector, HS-20 head-space sampler.
Chromatographic condition: taking polyethylene glycol (or polarity is close) as the capillary chromatographic column of fixer；Column temperature is 40 DEG C, is maintained
10min, injector temperature are 210 DEG C, and using flame ionization ditector (FID), detector temperature is 250 DEG C；Carrier gas is
Nitrogen, flow velocity 3.5ml/min；Ml headspace bottle equilibrium temperature is 80 DEG C, equilibration time 35min, split ratio 20:1.
Solution is prepared:
Blank solvent: it measures phosphoric acid 50ml, is diluted with water to 1000ml, shakes up to obtain the final product.
Positioning solution: it is each appropriate that precision weighs acetone, tetrahydrofuran and methylene chloride, respectively with the dilution of 5% phosphoric acid solution
It is made that methanol concentration is about 0.25mg/ml, tetrahydrofuran concentration is about 36 μ g/ml, concentration dichloromethane is about the molten of 30 μ g/ml
Liquid shakes up the positioning solution up to each solvent.
Reference substance solution: it is each appropriate that precision weighs acetone, tetrahydrofuran and methylene chloride, is diluted and is made with 5% phosphoric acid solution
Control is used as at, containing about the mixed solution of methanol 0.25mg, 36 μ g of tetrahydrofuran, 30 μ g of methylene chloride, shaking up in every 1ml
Product solution.
Test solution: precision weighs this product about 1.0g, sets in 20ml measuring bottle, adds 5% phosphoric acid solution to dissolve and is diluted to
Scale shakes up to obtain the final product.
1 system suitability of embodiment and specificity test
Precision measures blank solvent, positioning solution and acetone, tetrahydrofuran and methylene chloride mixed reference substance solution,
2ml is respectively taken, headspace sampling records chromatogram respectively.The available preferable separation of each component, each group under above-mentioned chromatographic condition
Point retention time and separating degree are shown in Table 1, and system suitability map is shown in attached drawing 1.
1 system suitability of table and specificity test result
Interpretation of result: blank solvent is noiseless to each residual solvent blob detection as the result is shown, and test solution only detects third
Ketone peak；Mixed reference substance solution continuous sample introduction 6 times, the peak-to-peak separating degree of adjacent solvent is all larger than 1.5, acetone, tetrahydrofuran, two
The RSD of chloromethanes peak area is respectively 3.0%, 4.0%, 8.6%, respectively less than 10.0%, the system suitability of this method and specially
Attribute is good, meets the requirements.
The detection of embodiment 2 limit and quantitative limit test
With signal-to-noise ratio S/N=3 calculate detection limit, with signal-to-noise ratio S/N=10 calculate quantitative limit, successively respectively dilute acetone,
The mixing reference substance liquid of tetrahydrofuran and methylene chloride.Take 2ml headspace sampling.Record chromatogram, detection limit and quantitative limit measurement
It the results are shown in Table 2-3.
The detection limit measurement result of table 2
3 quantitative limit measurement result of table
Interpretation of result: test result is shown, in the residual solvent analysis method, acetone, tetrahydrofuran, methylene chloride
Detection limit is respectively equivalent to 2.001ppm, 1.627ppm, 2.743ppm of sample concentration, and quantitative limit is respectively equivalent to sample concentration
7.845ppm, 4.849ppm, 10.619ppm.Therefore the residual solvent sensitivity of analytical method is good.
Embodiment 3 is linear and range is tested
It takes the mixing reference substance liquid of acetone, tetrahydrofuran and methylene chloride appropriate, is successively diluted to seven with 5% phosphoric acid solution
The solution of a series of concentrations.Sample introduction in the accurate solution 2ml top set empty bottle for measuring each concentration respectively, records chromatogram, with control
Product peak area is ordinate, and acetone, tetrahydrofuran and methylene chloride reference substance concentration are that abscissa does linear regression.As a result such as
Under:
Acetone regression equation: y=5028.9616x -16801.0853, coefficient R=0.9996, y intercept/100%
The absolute value of concentration-response value: 1.4%.The RSD of each concentration level response factor is 7.0%.Conclusion: acetone is in 0.5026 μ g/
Linear relationship between the μ of ml~301.5 g/ml (i.e. quantitative limit to sample introduction concentration 120%) concentration is good.
Tetrahydrofuran regression equation: coefficient R=0.9988 y=9909.0236x -2183.7219, y intercept/
The absolute value of 100% concentration-response value: 0.6%.The RSD of each concentration level response factor is 3.6%.Conclusion: tetrahydrofuran exists
Linear relationship between 0.3678 μ of μ g/ml~44.13 g/ml (i.e. quantitative limit to sample introduction concentration 120%) concentration is good.
Methylene chloride regression equation: y=5788.6169x -7034.0179 coefficient R=0.9962y y-intercept/
The absolute value of 100% concentration-response value: 4.2%.The RSD of each concentration level response factor is 14.2%.Conclusion: methylene chloride exists
Linear relationship between 0.6002 μ of μ g/ml~36.01 g/ml (i.e. quantitative limit to sample introduction concentration 120%) is good.
Interpretation of result: test result shows that in the residual solvent analysis method, acetone, tetrahydrofuran, methylene chloride exist
Within the scope of quantitative limit concentration to 120% sample concentration, concentration and the coefficient R of peak area equation of linear regression are all larger than
0.99, the absolute value of the ratio between the y intercept of each linear equation and 100% concentration-response value is respectively 1.4%, 0.6%, 4.2%,
Respectively less than 10.0%, the RSD value of each each linear concentration peak area response factor of solvent is respectively less than 20.0%.Therefore this product residual solvent
Analysis method in quantitative limit concentration to 120% range of sample introduction concentration, peak area and sample concentration it is linear good, conform to
It asks.
4 precision test of embodiment
4.1 repetitive test
Precision weighs Vardenafil hydrochloric acid about 1.0g and sets in 20ml measuring bottle, and acetone, tetrahydrofuran, methylene chloride control is added
Product mixed solution 0.5ml, dissolves and is diluted to 5% phosphoric acid solution scale, shake up, as mark-on test solution.Parallel 6
Part.2ml headspace sampling is taken, chromatogram is recorded.Measurement result is shown in Table 4-6.
4 acetone repetitive test result of table
5 tetrahydrofuran repetitive test result of table
6 methylene chloride repetitive test result of table
Interpretation of result: acetone, tetrahydrofuran and dichloromethane in 6 parts of same concentrations mark-on test solutions in repetitive test
The rate of recovery of alkane is between 80.0%~120.0%, and the RSD of the rate of recovery is respectively less than 10.0%, and repetitive test result meets
It is required that.
4.2 Intermediate precision
Intermediate precision test replacement analysis personnel, analysis date, Intermediate precision test apparatus condition and repeatability are tried
It tests identical.Precision measures 2ml mark-on test solution, and headspace sampling records chromatogram.Measurement result is shown in Table 7-9.
7 Intermediate precision acetone test result (analyst 2) of table
8 Intermediate precision tetrahydrofuran test result (analyst 2) of table
9 Intermediate precision methylene chloride test result (analyst 2) of table
Interpretation of result: acetone, tetrahydro in 6 parts of same concentrations mark-on test solutions in the test of 2 Intermediate precision of analyst
The rate of recovery of furans and methylene chloride is between 80.0~120.0%, and the RSD of the rate of recovery is respectively less than 10.0%, intermediate precision
The test result of degree meets verifying and requires.
In conjunction with the test data of two analysts, the average recovery rate of acetone is 95.7%, RSD in 12 parts of test solutions
It is 3.1%, the average recovery rate of tetrahydrofuran is 96.3%, RSD 3.4% in 12 parts of test solutions, and 12 parts of test samples are molten
The average recovery rate of methylene chloride is 93.0%, RSD 5.5% in liquid.Each solvent average recovery rate exists in 12 parts of samples
Between 90.0%~110.0%, RSD is respectively less than 10.0%, and the precision of the residual solvent analysis method is good, meets the requirements.
5 accuracy test of embodiment
Claim totally 9 parts of close weighing Vardenafil hydrochloric acid 1.0g, it is mixed to be separately added into acetone, tetrahydrofuran, methylene chloride reference substance
It closes solution 0.4,0.5,0.6ml and is placed in 20ml measuring bottle, 3 parts of operation repetitive, scale is dissolved and be diluted to 5% phosphoric acid solution, is shaken
It is even, as rate of recovery sample solution.2ml headspace sampling is taken, chromatogram is recorded, the rate of recovery is calculated by following formula.Measurement result is shown in Table
10-12.Rate of recovery %=(measured amount-sample size)/additional amount × 100%
10 acetone recovery test result of table
11 tetrahydrofuran recovery test result of table
12 methylene chloride recovery test result of table
Interpretation of result: within the scope of 80%~120% concentration level in three various concentrations the acetone rate of recovery 92.59%
Between~99.28%, average value 96.5%, RSD 2.5%,；The tetrahydrofuran rate of recovery 93.26%~103.53% it
Between, average value 98.7%, RSD 3.6%；Between 85.29%~105.80%, average value is the methylene chloride rate of recovery
95.2%, RSD 7.7%.The rate of recovery of each 9 parts of samples of solvent between 80%~120%, the rate of recovery of 9 parts of samples
RSD value is respectively less than 10%, meets the requirements, therefore the accuracy of the residual solvent analysis method is good.
6 sample solvent residue detection of embodiment
Take 3 batches of Vardenafil hydrochloric acid bulk pharmaceutical chemicals sample detections of pilot scale, by heretofore described residual solvent detection method into
Row detection, the results are shown in Table 13.
13 pilot scale of table, 3 batches of sample dissolvent residual measurement results
| Title | Sample 1 | Sample 2 | Sample 3 |
| Acetone | 0.006% | 0.010% | 0.03% |
| Tetrahydrofuran | It is not detected | It is not detected | It is not detected |
| Methylene chloride | It is not detected | It is not detected | It is not detected |
Detailed description of the invention
Fig. 1 is Vardenafil hydrochloric acid chemical molecular formula；
Fig. 2 is acetone, tetrahydrofuran and methylene chloride residual solvent specificity Typical gas chromatograph figure.
Claims (5)
1. a kind of method for measuring Vardenafil hydrochloric acid organic solvent residual in raw medicine content, which is characterized in that including following
Step: the Vardenafil hydrochloric acid bulk pharmaceutical chemicals are analyzed by capillary gas chromatography, to obtain chromatogram；And
Based on the chromatogram, organic solvent residual content in the Vardenafil hydrochloric acid is determined；
Wherein, the Vardenafil hydrochloric acid bulk pharmaceutical chemicals are provided in the form of test solution, and the test solution is salt
5% phosphoric acid solution of sour Vardenafil；
The organic solvent includes acetone, tetrahydrofuran and methylene chloride；
The capillary gas chromatography uses following condition:
Detector is flame ionization ditector, and detector temperature is 200-300 DEG C, and injector temperature is 150-250 DEG C, color
Composing column is capillary chromatographic column similar in polyethylene glycol polarity, and column temperature is 30-50 DEG C, maintains 5-20min, carrier gas is nitrogen, helium
Gas or argon gas, flow rate of carrier gas 1-10ml/min, equilibrium temperature are 60-140 DEG C, equilibration time 20-60min.
2. the method according to claim 1, wherein the capillary gas chromatography uses following condition:
Detector temperature is 250 DEG C, and injector temperature is 210 DEG C, and chromatographic column is polyethylene glycol capillary chromatographic column, column temperature 40
DEG C, 10min is maintained, carrier gas is nitrogen, and flow rate of carrier gas 3.5ml/min, equilibrium temperature is 80 DEG C, equilibration time 35min.
3. the method according to claim 1, wherein the capillary gas chromatography is molten using standard control
Liquid, the standard control solution are the mixed solutions of acetone, tetrahydrofuran and methylene chloride, and are based on every milliliter of mixing
Solution, respectively 3 microgram containing 0.25 milligram of acetone, 36 microgram of tetrahydrofuran and methylene chloride.
4. the method according to claim 1, wherein being based on every milliliter of institute in the capillary gas chromatography
Test solution is stated, the content of Vardenafil hydrochloric acid is 0.05 gram.
5. a kind of method for measuring Vardenafil hydrochloric acid organic solvent residual in raw medicine content, which is characterized in that this method packet
It includes:
It take polyethylene glycol (or polarity is close) as the capillary chromatographic column of fixer；Column temperature is 40 DEG C, maintains 10min, injection port
Temperature is 210 DEG C, and using flame ionization ditector, detector temperature is 250 DEG C；Carrier gas is nitrogen, flow velocity 3.5ml/
min；Ml headspace bottle equilibrium temperature is 80 DEG C, equilibration time 35min, split ratio 20:1；
Prepare placebo solution:
It measures 5% phosphoric acid solution of 2ml to set in the chromatographic ml headspace bottle, as the placebo solution；
Prepare standard control solution:
Precision measurement acetone, tetrahydrofuran and methylene chloride are each appropriate, are quantitatively diluted and are made in every 1 milliliter with 5% phosphoric acid solution
The about mixed solution containing 0.25 milligram of acetone, 36 microgram of tetrahydrofuran and 30 microgram of methylene chloride respectively, as the standard pair
According to solution；
Prepare test solution:
Precision weighs the Vardenafil hydrochloric acid, and addition 5% phosphoric acid solution, which is dissolved and is quantitatively diluted in every 1 milliliter, to be contained
0.05 gram of solution, as the test sample solution；And injecting chromatograph, chromatogram is obtained, according to the chromatogram meter
Calculation obtains the type and content of Elements in Organic Solvents in the test sample solution；
Wherein, the Elements in Organic Solvents includes acetone, tetrahydrofuran and methylene chloride.
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