CN115097027A - Gas chromatography detection method for residual solvent in sildenafil citrate bulk drug - Google Patents
Gas chromatography detection method for residual solvent in sildenafil citrate bulk drug Download PDFInfo
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Abstract
The invention relates to the technical field of drug analysis and detection, and provides a gas chromatography detection method for residual solvent in sildenafil citrate bulk drug. Through the technical scheme, the quantitative detection of the residual quantity of 4 solvents including methanol, ethanol, dichloromethane and cyclohexane in the sildenafil citrate bulk drug is realized, and the problem of interference of the peak of the thermal degradation product of the sildenafil citrate bulk drug on the detection of the residual solvent is effectively avoided.
Description
Technical Field
The invention relates to the technical field of drug analysis and detection, in particular to a gas chromatography detection method for residual solvents in sildenafil citrate bulk drugs.
Background
Sildenafil citrate was developed by the company pfizer and used clinically for the treatment of ED (erectile dysfunction). Sildenafil citrate is an oral PDE-5 (phosphodiesterase-5) inhibitor, and its activity is reduced by highly selective inhibition of PDE-5, thereby reducing degradation of cyclic guanosine monophosphate which regulates smooth muscle relaxation, increasing cyclic guanosine monophosphate concentration in the corpus cavernosum of the penis, relaxing blood engorgement of smooth muscle in the corpus cavernosum, and further reducing the occurrence of ED.
Methanol, ethanol, dichloromethane and cyclohexane are needed in the sildenafil citrate raw material medicine synthesis and refining process, and in order to ensure the safety of the sildenafil citrate raw material medicine, the residual amounts of the four solvents in the raw material medicine need to be controlled within a reasonable limit range, so that the quality of the sildenafil citrate raw material medicine is improved.
Disclosure of Invention
The invention provides a gas chromatography detection method for residual solvent in sildenafil citrate bulk drug, which realizes quantitative detection of residual amounts of 4 solvents including methanol, ethanol, dichloromethane and cyclohexane in the sildenafil citrate bulk drug and effectively avoids the problem of interference of peak appearance of thermal degradation products of the sildenafil citrate bulk drug on detection of the residual solvent.
The technical scheme of the invention is as follows:
the invention provides a gas chromatography detection method of residual solvent in sildenafil citrate bulk drug, which comprises the steps of adding the sildenafil citrate bulk drug into N, N-dimethylformamide for dissolving to obtain a sample solution, and detecting by adopting headspace gas chromatography to determine the residual amount of methanol, ethanol, dichloromethane and cyclohexane in the sildenafil citrate bulk drug.
As a further technical scheme, the detection by adopting the headspace gas chromatography comprises the following steps:
s1, preparation of a mixed reference solution: respectively taking methanol, ethanol, dichloromethane and cyclohexane standard substances, adding N, N-dimethylformamide to dissolve, and fixing the volume to obtain methanol, ethanol, dichloromethane and cyclohexane reference substance solutions; then mixing methanol, ethanol, dichloromethane and cyclohexane reference substance solution, diluting with N, N-dimethylformamide, and fixing the volume to obtain mixed reference substance solution;
s2, detecting a sample: and respectively detecting the sample solution and the mixed reference solution by adopting a headspace gas chromatography, and quantifying by adopting an external standard method to determine the residual amounts of methanol, ethanol, dichloromethane and cyclohexane in the sildenafil citrate bulk drug.
As a further technical scheme, the concentration of the sildenafil citrate bulk drug in the sample solution is 30-50 mg/mL.
As a further technical scheme, in the headspace gas chromatography, the temperature-raising program of the chromatographic column is as follows: the initial temperature is 30-40 ℃, the temperature is maintained for 5-10 min, the temperature is increased to 120-180 ℃ at the speed of 10-20 ℃/min, the temperature is maintained for 1-5 min, the temperature is increased to 200-220 ℃ at the speed of 15-30 ℃/min, and the temperature is maintained for 10-20 min.
As a further technical scheme, in the headspace gas chromatography, the headspace equilibrium temperature is 60-100 ℃, and the equilibrium time is 20-60 min.
According to a further technical scheme, in the headspace gas chromatography, a carrier gas is nitrogen, the flow rate is 1.0-3.0 mL/min, and the split ratio is 1: 1-20: 1.
As a further technical scheme, in the headspace gas chromatography, the temperature of a quantitative ring is 80-120 ℃, the temperature of a transmission pipeline is 90-130 ℃, the temperature of a sample inlet is 110-200 ℃, and the temperature of a detector is 200-250 ℃.
As a further technical scheme, in the headspace gas chromatography, a chromatographic column is a capillary column taking 6% cyanopropylphenyl-94% dimethylpolysiloxane as a stationary phase.
As a further technical scheme, the chromatographic column is a medium polarity chromatographic column, the length of the chromatographic column is 30-60 m, the thickness of the chromatographic column is 1.8-3 mu m, and the inner diameter of the chromatographic column is 0.32-0.53 mm.
The working principle and the beneficial effects of the invention are as follows:
1. according to the invention, aiming at the structural characteristics of sildenafil citrate bulk drug and the characteristic that low-boiling-point degradants are generated by thermal degradation, N-dimethylformamide is adopted as a solvent to prepare a sample solution and a reference solution, and meanwhile, a headspace sampling method is adopted to detect residual solvents in the sildenafil citrate bulk drug by gas chromatography, so that the problem of interference of peaks of thermal degradation products of the sildenafil citrate bulk drug on the detection of the residual solvents can be effectively avoided.
2. In the invention, the detection method and the detection conditions of the gas chromatography detection of the sildenafil citrate bulk drug are optimized, so that the method can simultaneously determine the residual quantity of four solvents such as methanol, ethanol, dichloromethane and cyclohexane in the sildenafil citrate bulk drug, and the method is verified by tests such as a system applicability test, a detection limit and quantification limit test, a linear range test, a precision test, an accuracy test and a durability test.
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The present invention will be described in further detail with reference to the accompanying drawings and specific embodiments.
FIG. 1 is a chromatogram of a mixed control solution in a system applicability test of the present invention;
FIG. 2 is a chromatogram for determining residual solvent in sildenafil citrate bulk drug when N, N-dimethylformamide is used as diluent;
FIG. 3 is a chromatogram for measuring the residual solvent in sildenafil citrate bulk drug when the diluent is dimethyl sulfoxide;
FIG. 4 is a chromatogram for determining residual solvent in sildenafil citrate bulk drug when N-methylpyrrolidone is used as diluent;
FIG. 5 is a chromatogram for determining residual solvent in sildenafil citrate bulk drug by headspace sampling;
FIG. 6 is a chromatogram for determining residual solvent in sildenafil citrate bulk drug by direct sample injection;
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any inventive step, are intended to be within the scope of the present invention.
Example 1
Determination of residual solvent in sildenafil citrate bulk drug
1. Preparation of the solution
Test solution: putting 80mg of sildenafil citrate raw material medicine into a 20mL headspace bottle, adding 2mL of N, N-dimethylformamide for dissolving, and sealing to prepare a test solution, wherein the concentration of the sildenafil citrate raw material medicine in the solution is 40 mg/mL;
methanol control stock solution: weighing 240mg of methanol, placing the methanol in a 20mL volumetric flask filled with 5mL of N, N-dimethylformamide, and performing constant volume by using the N, N-dimethylformamide to obtain a methanol reference substance stock solution, wherein the concentration of the methanol in the solution is 12 mg/mL;
ethanol control stock solution: weighing 400mg of methanol, placing the methanol in a 20mL volumetric flask filled with 5mL of N, N-dimethylformamide, and performing constant volume by using the N, N-dimethylformamide to obtain an ethanol reference substance stock solution, wherein the concentration of ethanol in the solution is 20 mg/mL;
dichloromethane control stock solution: weighing 120mg of dichloromethane, placing the dichloromethane into a 50mL volumetric flask filled with 10mL of N, N-dimethylformamide, and carrying out constant volume by using the N, N-dimethylformamide to obtain a dichloromethane reference substance stock solution, wherein the concentration of dichloromethane in the solution is 2.4 mg/mL;
cyclohexane control stock solution: weighing 780mg of cyclohexane, placing the cyclohexane in a 50mL volumetric flask filled with 10mL of N, N-dimethylformamide, and carrying out constant volume with the N, N-dimethylformamide to obtain a cyclohexane reference substance stock solution, wherein the concentration of the cyclohexane in the solution is 15.6 mg/mL;
mix control stock solution: 5mL of each control stock solution was weighed into a 50mL volumetric flask, and the volume was determined with N, N-dimethylformamide to obtain mixed control stock solutions in which the concentrations of methanol, ethanol, dichloromethane, and cyclohexane were 1200. mu.g/mL, 2000. mu.g/mL of ethanol, 240. mu.g/mL of dichloromethane, and 1560. mu.g/mL of cyclohexane, respectively.
Mixing the reference solution: weighing 2mL of the mixed reference stock solution, placing the mixed reference stock solution in a 20mL volumetric flask, using N, N-dimethylformamide for constant volume to obtain a mixed reference solution, wherein the concentrations of methanol, ethanol, dichloromethane and cyclohexane in the mixed reference solution are respectively 120 mu g/mL, 200 mu g/mL of ethanol, 24 mu g/mL of dichloromethane and 156 mu g/mL of cyclohexane, placing 2mL of the mixed reference solution in a headspace flask, and sealing.
2. Detection of
Detecting the mixed reference substance solution and the test substance solution by adopting a headspace gas chromatography, wherein the detection conditions are as follows:
and (3) chromatographic column: a capillary column using 6% cyanopropylphenyl-94% dimethylpolysiloxane as a stationary liquid was used as a chromatographic column (60 m.times.0.53 mm.times.3 μm);
temperature programming: the initial temperature is 35 ℃, the temperature is maintained for 10min, the temperature is raised to 150 ℃ at the speed of 10 ℃/min, the temperature is maintained for 2min, the temperature is raised to 210 ℃ at the speed of 20 ℃/min, and the temperature is maintained for 5 min;
carrier gas: nitrogen gas;
flow rate: 2.0 mL/min;
the split ratio is as follows: 10: 1;
headspace bottle equilibrium temperature: 80 ℃;
and (3) balancing time: 30 min;
quantitative ring temperature: 90 ℃;
temperature of the transmission pipeline: 100 ℃;
sample inlet temperature: 120 ℃;
detector temperature: 220 ℃;
cycle time: and (5) 50 min.
Recording a chromatogram, and calculating the content of the residual solvent by peak area according to an external standard method, wherein the calculation formula is as follows:
X＝(A for supplying to ×W For is to ×V For supplying to )/(W For supplying to ×A To pair ×V To pair )×100％；
In the formula: x is the content of residual solvent in sildenafil citrate,%;
A for supplying to Is the peak area of the solvent to be detected in the chromatogram of the test solution;
A to pair The peak area average value of the solvent to be detected in the mixed reference substance solution chromatogram;
W for supplying to Weighing sample amount (mg) for a sample;
W for is to The weight (mg) of the solvent to be tested is mixed with the reference solution;
V for supplying to Is the dilution multiple of the test solution;
V to pair Is the dilution factor of the mixed control solution.
3. Method verification
3.1 System suitability test
(1) Test method
And continuously injecting the mixed reference substance solution into 6 needles, recording a chromatogram, and calculating the RSD value of the peak area.
(2) Test requirements
The peak area RSD value of each solvent of the 6-needle mixed reference solution is not more than 10.0 percent; the separation between solvent peaks should be greater than 1.5; the theoretical plate number of each solvent peak should be not less than 5000.
(3) Test results
The chromatogram is shown in fig. 1, and the peak area RSD values of the solvents in the 6-pin mixed control solution are respectively: methanol RSD ═ 0.9%, ethanol RSD ═ 1.3%, dichloromethane RSD ═ 3.3%, cyclohexane RSD ═ 1.3%; the minimum degree of separation of each residual solvent peak is greater than 1.5; the theoretical plate number of each solvent peak is more than 5000; the requirements are met.
3.2 testing detection limit and quantitative limit
(1) Test method
And (3) referring to the signal-to-noise ratio of the residual solvent of the mixed reference solution, and respectively diluting each solvent reference stock solution until the peak signal-to-noise ratio (S/N) of each residual solvent is 10:1, wherein the corresponding solution concentration is the quantitative limit of each residual solvent. And (3) referring to the signal-to-noise ratio of each residual solvent in the quantitative limiting solution, and diluting the quantitative limiting solution until the corresponding solution concentration is the detection limit when the signal-to-noise ratio (S/N) is 3: 1.
(2) Test requirements
The detection limit signal-to-noise ratio S/N is 3;
the quantitative limit signal-to-noise ratio S/N is 10.
(3) Test results
The detection limit and quantitation limit results for each residual solvent are shown in the following table:
TABLE 1 detection Limit and quantitation Limit test results
| Detecting items | Methanol | Ethanol | Methylene dichloride | Cyclohexane |
| Detection limit | 1.12μg/mL | 1.0μg/mL | 2.0μg/mL | 1.0μg/mL |
| Limit of quantification | 3.35μg/mL | 2.0μg/mL | 6.6μg/mL | 3.3μg/mL |
3.3 Linear Range test
(1) Test method
Linear 1: the quantitative limiting concentration solution was taken as a linear 1 solution. The diluent is N, N-dimethylformamide.
Linear 2 (20% level): precisely weighing 1.0mL of the mixed reference substance stock solution in a 50mL measuring flask, diluting to scale with diluent, and mixing.
Linear 3 (50% level): precisely measuring 1.0mL of the mixed reference substance stock solution in a 20mL measuring flask, diluting to scale with a diluent, and mixing uniformly to obtain the final product.
Linear 4 (80% level): precisely weighing 2.0mL of the mixed reference substance stock solution in a 25mL measuring flask, diluting to scale with diluent, and mixing.
Linear 5 (100% level): precisely weighing 2.0mL of the mixed reference substance stock solution in a 20mL measuring flask, diluting to scale with diluent, and mixing.
Linear 6 (150% level): precisely weighing 3.0mL of the mixed reference substance stock solution in a 20mL measuring flask, diluting to scale with a diluent, and mixing uniformly to obtain the final product.
And precisely transferring 2mL of the linear 1-6 solution, placing the linear 1-6 solution in a headspace bottle, sealing, introducing a headspace sample, recording a chromatogram, and performing linear regression on peak areas according to the concentration of each residual solvent.
(2) Test requirements
The linearity relation of each residual solvent is good, and the correlation coefficient R is more than 0.99.
(3) Test results
Taking the peak area of a reference substance as a vertical coordinate and the concentrations of the methanol, ethanol, dichloromethane and cyclohexane reference substances as a horizontal coordinate, establishing a linear regression curve, and obtaining the test results shown in the following table:
TABLE 2 Linear test results
3.4, precision test
(1) Test method
Adding a standard solution into a test sample: 80mg of the test sample is precisely weighed and placed in a 20mL headspace bottle, 2mL of mixed reference solution is precisely added to dissolve, and 6 parts are prepared in parallel after sealing. And (4) after headspace sample injection in sequence, recording a chromatogram, and calculating the RSD value of the peak area of each residual solvent.
(2) Test requirements
The RSD value for each residual solvent peak area should be less than 10%.
(3) Test results
The results of the precision tests are given in the following table:
TABLE 3 results of precision test
| Detecting items | Methanol | Ethanol | Methylene dichloride | Cyclohexane |
| Precision degree | RSD＝0.80％ | RSD＝0.94％ | RSD＝0.56％ | RSD＝0.97％ |
3.5 accuracy test
(1) Test method
20% recovery stock solution: precisely transferring 2.0mL of the mixed reference stock solution into a 100mL measuring flask, diluting to scale with diluent, and mixing.
120% recovery stock solution: precisely transferring 3.0mL of the mixed reference stock solution into a 25mL measuring flask, diluting the mixed reference stock solution to a scale with a diluent, and uniformly mixing.
Recovery solution 1 (20% level): taking 80mg of a sample, precisely weighing, placing in a top empty bottle, adding 2mL of 20% recovery rate stock solution for dissolving, sealing, and shaking uniformly to obtain the final product. 3 parts are prepared in parallel.
Recovery solution 2 (100% level): and (3) precisely weighing 80mg of a sample, placing the sample in a headspace bottle, adding 2mL of mixed control solution for dissolving, sealing and shaking up to obtain the test solution. 3 parts are prepared in parallel.
Recovery solution 3 (120% level): taking 80mg of a sample, precisely weighing, placing in a top empty bottle, adding 2mL of 120% recovery rate stock solution for dissolving, sealing, and shaking uniformly to obtain the final product. 3 parts are prepared in parallel.
(2) Test requirements
The recovery rate of 9 parts of solution with 3 concentrations is 80-120%, and the RSD value is not more than 10%.
(3) Test results
The accuracy test results are shown in the following table:
TABLE 4 accuracy test results
| Detecting items | Methanol | Ethanol | Methylene dichloride | Cyclohexane |
| Recovery rate | 97.5％～102.1％ | 98.9％～100.6％ | 97.5％～100.1％ | 92.6％～100.6％ |
| RSD | 1.5％ | 0.8％ | 1.0％ | 2.4％ |
3.6 durability test
(1) Test method
The sample solution and the mixed control solution were placed in a headspace bottle, respectively, sealed, the headspace heated and injected into a gas chromatograph, and the chromatograms were recorded under otherwise unchanged conditions by changing the chromatographic column (DB-62460 m × 0.53mm × 3 μm, DB-62430m × 0.32mm × 1.8 μm, respectively), the carrier gas flow rate (1.8 mL/min and 2.2mL/min, respectively), the headspace equilibration time (25 min and 35min, respectively), the initial column temperature (30 ℃ and 40 ℃ respectively) and the injection port temperature (110 ℃ and 130 ℃ respectively).
(2) Test requirements
When the measuring conditions have small changes, the system applicability and the sample detection result both meet the requirements.
(3) Test results
TABLE 5 durability test results
| Changing conditions | Methanol (%) | Ethanol (%) | Methylene chloride (%) | Cyclohexane (%) |
| Chromatographic column (DB-62460 m x 0.53mm x 3 μm) | Not detected out | 0.05％ | Not detected out | Not detected out |
| Chromatographic column (DB-62430 m x 0.32mm x 1.8 μm) | Not detected out | 0.06％ | Not detected out | Not detected out |
| Flow rate 1.8mL/min | Not detected out | 0.05％ | Not detected | Not detected out |
| Flow rate 2.2mL/min | Not detected | 0.05％ | Not detected | Not detected |
| Headspace balance time 25min | Not detected out | 0.05％ | Not detected out | Not detected out |
| Headspace balance time 35min | Not detected out | 0.05％ | Not detected out | Not detected out |
| |
Not detected out | 0.05％ | Not detected out | Not detected out |
| |
Not detected out | 0.05％ | Not detected out | Not detected |
| The temperature of a sample inlet is 110 DEG C | Not detected out | 0.05％ | Not detected out | Not detected out |
| The temperature of a sample inlet is 130 DEG C | Not detected out | 0.05％ | Not detected | Not detected out |
4. Results of sample testing
Taking 3 batches of sildenafil citrate raw material samples (the production batches are NSC200906, NSC200907 and NSC200908 respectively), detecting the content of residual solvent in the samples according to the method, and obtaining the following results:
TABLE 6 measurement results of residual solvent content in samples
| Sample batch number | Methanol | Ethanol | Methylene dichloride | Cyclohexane |
| NSC200906 | Not detected out | 0.05％ | Not detected out | Not detected out |
| NSC200907 | Not detected out | 0.06％ | Not detected | Not detected out |
| NSC200908 | Not detected | 0.05％ | Not detected | Not detected out |
(1) Experimental methods
The following experimental and control groups were set up:
experimental groups: as in example 1, the diluent was N, N-dimethylformamide;
control group 1: the only difference from example 1 is that the diluent is dimethyl sulfoxide;
control group 2: the only difference from example 1 is that the diluent is N-methylpyrrolidone;
the detection method of the experimental group and the control group is a direct sample injection method, the sample injection amount is 1 mu L, and the gas chromatography detection conditions are the same as those of the example 1.
(2) Results of the experiment
Chromatograms of the experimental group and the control groups 1 and 2 are shown in figures 2-4, and it can be seen from the chromatograms that the chromatograms of the control groups 1 and 2 both have a large peak of sildenafil citrate thermal degradation product, which interferes with the detection of residual solvent in sildenafil citrate bulk drug, and N, N-dimethylformamide is used as diluent, the peak of the sildenafil citrate thermal degradation product in the obtained chromatograms is minimum, which shows that the interference problem of the sildenafil citrate thermal degradation product on the detection of residual solvent can be effectively reduced by adopting the diluent and specific detection conditions of the invention.
(1) Experimental methods
The following experimental and control groups were set up:
experimental groups: in the same way as example 1, the sample injection mode is headspace sample injection;
control group 3: the difference from the example 1 is only that the sample injection mode is direct sample injection;
the conditions of gas chromatography detection in the experimental group and the control group 3 were the same as in example 1.
(2) Results of the experiment
The chromatograms of the experimental group and the control group 3 are shown in figures 5-6, and it can be seen from the chromatograms that the chromatogram of the control group 3 has a peak of sildenafil citrate thermal degradation product, which interferes with the detection of residual solvent in sildenafil citrate bulk drug, and the experimental group adopts a headspace sampling method, and the obtained chromatogram has no peak of sildenafil citrate thermal degradation product, which indicates that the interference of sildenafil citrate thermal degradation product with the detection of residual solvent can be effectively solved by adopting the headspace sampling method and specific detection conditions of the invention.
Aiming at a thermal degradation product interference peak generated when a direct sample injection mode is adopted to detect a residual solvent in a sildenafil citrate bulk drug, a GC-MS method is used for analysis, and the result shows that the peak structure is consistent with the sildenafil citrate mother ring structure, and the peak structure is determined to be a chromatographic peak generated by the degradation of the sildenafil citrate at the high temperature of a sample injection port by combining the condition of the occurrence of a direct sample injection test because the sildenafil citrate bulk drug is not used in the synthesis process.
(1) Experimental methods
The following experimental and control groups were set up:
experimental groups: as in example 1, the column temperature program was: the initial temperature is 35 ℃, the temperature is maintained for 10min, the temperature is increased to 150 ℃ at the speed of 10 ℃/min, the temperature is maintained for 2min, the temperature is increased to 210 ℃ at the speed of 20 ℃/min, and the temperature is maintained for 5 min;
control group 4: the only difference from example 1 is that the column temperature program is: the initial temperature is 30 ℃, the temperature is maintained for 5min, the temperature is raised to 200 ℃ at the speed of 45 ℃/min, and the temperature is maintained for 10 min;
control group 5: the only difference from example 1 is that the temperature program of the column is: the initial temperature is 40 ℃, the temperature is maintained for 6min, the temperature is raised to 220 ℃ at the speed of 60 ℃/min, and the temperature is maintained for 6 min;
control group 6: the only difference from example 1 is that the temperature program of the column is: the initial temperature is 35 ℃, the temperature is maintained for 10min, the temperature is raised to 210 ℃ at the speed of 10 ℃/min, and the temperature is maintained for 5 min;
control group 7: the only difference from example 1 is that the column temperature program is: the initial temperature is 35 ℃, the temperature is maintained for 10min, the temperature is raised to 210 ℃ at the speed of 20 ℃/min, and the temperature is maintained for 5 min;
adopting a headspace sample injection mode, taking a mixed reference substance solution of methanol, ethanol, dichloromethane and cyclohexane, respectively carrying out headspace sample injection detection under the chromatographic conditions of an experimental group and a reference group, and comparing the chromatogram maps.
(2) Results of the experiment
The chromatogram analysis shows that the chromatographic peaks of methanol, ethanol, dichloromethane and cyclohexane in the chromatograms obtained from the control groups 4 and 5 can not be completely separated, the chromatographic peaks of residual solvent in the chromatograms obtained from the control groups 6 and 7 can not be completely separated, the detection requirement of residual solvent in sildenafil citrate bulk drug can not be met, the chromatographic peaks of four solvents in the chromatogram obtained from the experimental group can be completely separated and can also be completely separated from the solvent peaks, and the specific temperature-raising program of the chromatographic column is matched with a diluent and a headspace sample injection mode, so that the separation of methanol, ethanol, dichloromethane and cyclohexane in a sample can be well realized, and the quantitative detection of the residual quantity of methanol, ethanol, dichloromethane and cyclohexane in the sample can be realized.
The present invention is not limited to the above embodiments, and any modifications, equivalent substitutions, improvements, etc. within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (9)
1. The gas chromatography detection method for the residual solvent in the sildenafil citrate bulk drug is characterized in that the sildenafil citrate bulk drug is added into N, N-dimethylformamide to be dissolved to obtain a sample solution, and the headspace gas chromatography is adopted for detection to determine the residual amounts of methanol, ethanol, dichloromethane and cyclohexane in the sildenafil citrate bulk drug.
2. The gas chromatography detection method of residual solvent in sildenafil citrate bulk drug according to claim 1, characterized in that the detection by headspace gas chromatography comprises the following steps:
s1, preparation of a mixed reference solution: respectively taking methanol, ethanol, dichloromethane and cyclohexane standard substances, adding N, N-dimethylformamide to dissolve, and fixing the volume to obtain methanol, ethanol, dichloromethane and cyclohexane reference substance solutions; then mixing the methanol, the ethanol, the dichloromethane and the cyclohexane reference substance solution, diluting with N, N-dimethylformamide, and fixing the volume to obtain a mixed reference substance solution;
s2, detecting a sample: and respectively detecting the sample solution and the mixed reference solution by adopting a headspace gas chromatography, and quantifying by adopting an external standard method to determine the residual amounts of methanol, ethanol, dichloromethane and cyclohexane in the sildenafil citrate bulk drug.
3. The gas chromatography detection method of residual solvent in sildenafil citrate bulk drug according to claim 1, wherein the concentration of the sildenafil citrate bulk drug in the sample solution is 30-50 mg/mL.
4. The gas chromatography detection method of residual solvent in sildenafil citrate bulk drug according to claim 1, wherein in the headspace gas chromatography, the temperature-raising program of the chromatographic column is as follows: the initial temperature is 30-40 ℃, the temperature is maintained for 5-10 min, the temperature is increased to 120-180 ℃ at the speed of 10-20 ℃/min, the temperature is maintained for 1-5 min, the temperature is increased to 200-220 ℃ at the speed of 15-30 ℃/min, and the temperature is maintained for 10-20 min.
5. The gas chromatography detection method of residual solvents in sildenafil citrate bulk drug according to claim 4, wherein in the headspace gas chromatography, the headspace equilibrium temperature is 60-100 ℃ and the equilibrium time is 20-60 min.
6. The gas chromatography detection method of residual solvent in sildenafil citrate bulk drug according to claim 1, characterized in that in the headspace gas chromatography, the carrier gas is nitrogen, the flow rate is 1.0-3.0 mL/min, and the split ratio is 1: 1-20: 1.
7. The gas chromatography detection method of residual solvent in sildenafil citrate bulk drug according to claim 1, wherein in the headspace gas chromatography, the temperature of a quantitative ring is 80-120 ℃, the temperature of a transmission pipeline is 90-130 ℃, the temperature of a sample inlet is 110-200 ℃, and the temperature of a detector is 200-250 ℃.
8. The gas chromatography detection method of residual solvent in sildenafil citrate bulk drug according to claim 1, wherein in the headspace gas chromatography, the chromatographic column is a capillary column using 6% cyanopropylphenyl-94% dimethylpolysiloxane as a stationary phase.
9. The gas chromatography detection method of residual solvent in sildenafil citrate bulk drug according to claim 8, wherein the chromatographic column is a medium polarity chromatographic column, the length of the column is 30-60 m, the thickness of the membrane is 1.8-3 μm, and the inner diameter is 0.32-0.53 mm.
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| CN108614058A (en) * | 2018-06-19 | 2018-10-02 | 广西壮族自治区食品药品检验所 | Measure the headspace gas chromatography of glycine organic solvent residual in raw medicine amount |
| CN110320293A (en) * | 2019-06-28 | 2019-10-11 | 北京澳合药物研究院有限公司 | A kind of method of residual solvent in measurement phthalide analog compound |
| CN114137095A (en) * | 2020-09-03 | 2022-03-04 | 北京渼颜空间生物医药有限公司 | Method for efficiently detecting residual solvent in poly-L-lactic acid and preparation thereof |
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| CN108614058A (en) * | 2018-06-19 | 2018-10-02 | 广西壮族自治区食品药品检验所 | Measure the headspace gas chromatography of glycine organic solvent residual in raw medicine amount |
| CN110320293A (en) * | 2019-06-28 | 2019-10-11 | 北京澳合药物研究院有限公司 | A kind of method of residual solvent in measurement phthalide analog compound |
| CN114137095A (en) * | 2020-09-03 | 2022-03-04 | 北京渼颜空间生物医药有限公司 | Method for efficiently detecting residual solvent in poly-L-lactic acid and preparation thereof |
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