Method for measuring benzene residues in recovered acetone, toluene and ethanol in drug production process

Abstract

The invention discloses a determination method for recovering benzene residues in acetone, toluene and ethanol in a drug production process, and relates to the field of pharmacy, and the determination method comprises the following steps: S1, preparing a test solution: taking a test sample, placing the test sample in a small gas-phase sample injection bottle to obtain the test solution, and sealing the test solution; s2, the test solution is detected through gas chromatography, a chromatographic instrument adopted by the gas chromatography is a capillary column gas chromatographic instrument, the initial temperature of a chromatographic column of the capillary column gas chromatographic instrument is 40 DEG C, the temperature is maintained for 6 minutes, the temperature is increased to 180 DEG C at the speed of 60 DEG C per minute, and the temperature is maintained for 10 minutes; the invention provides a method for measuring benzene residues in recovered acetone, toluene and ethanol in a medicine production process, and a gradient heating technical scheme is adopted, so that the benzene residues in recovered solvents acetone, toluene and ethanol can be effectively detected, and the safety of medication is ensured.

Description

Technical Field

[0001] The invention relates to the pharmaceutical field, and in particular to a method for determining benzene residues in acetone, toluene and ethanol recovered during a drug production process. Background Art

[0002] Acetone, toluene, ethanol or one of them is often used in the production process of tazobactam, amoxicillin and clavulanate potassium. Acetone, toluene and ethanol need to be recycled after use. Acetone, toluene and ethanol may contain benzene. Benzene is a carcinogen. If it remains in the medicine, it will cause harm to the human body. For example, excessive benzene residues may induce malignant cell changes.

[0003] In order to better control the quality of tazobactam, amoxicillin and potassium clavulanate, it is necessary to provide a measurement method to detect benzene residues to ensure the safety of medication. However, there is currently no gas phase quantitative determination method for benzene residues in acetone, toluene and ethanol recovered during drug production on the market. Therefore, a method for determining benzene residues in acetone, toluene and ethanol recovered during drug production is urgently needed. Summary of the invention

[0004] In order to solve the above technical problems, the present invention provides a method for determining the residual benzene in acetone, toluene and ethanol recovered in a drug production process, comprising the following steps: S1. Prepare the test solution: take an appropriate amount of the test sample, put it into a gas phase injection vial, obtain the test solution, and seal it; S2. The test solution is detected by gas chromatography, and the chromatograph used in the gas chromatography is a capillary column gas chromatograph. The initial temperature of the chromatographic column of the capillary column gas chromatograph is 40°C, which is maintained for 6 minutes, and then the temperature is increased to 180°C at a rate of 60°C per minute and maintained for 10 minutes.

[0005] Furthermore, the test samples are acetone, toluene and ethanol recovered during the production process of tazobactam.

[0006] Furthermore, the test sample is acetone recovered during the production process of amoxicillin.

[0007] Furthermore, the test samples are acetone and toluene recovered during the production process of potassium clavulanate.

[0008] Furthermore, the chromatographic column of the capillary column gas chromatograph uses 5% phenyl dimethyl polysiloxane as the stationary liquid.

[0009] Furthermore, the carrier gas of the capillary column gas chromatograph is nitrogen, and the flow rate of the carrier gas is 3.9-4.1 ml / min.

[0010] Furthermore, the capillary column gas chromatograph adopts a hydrogen flame ionization detector.

[0011] Furthermore, the injection mode of the gas chromatography is split injection, and the injection volume is 0.8 μl.

[0012] Furthermore, the injection port temperature of the gas chromatography is 275°C-285°C, and the detector temperature is 275°C-285°C.

[0013] Compared with the prior art, the present invention has the following beneficial effects: 1. The present invention provides a method for determining benzene residues in acetone, toluene and ethanol recovered in a drug production process, and adopts a gradient heating technical solution, which can effectively detect benzene residues in the recovered solvents acetone, toluene and ethanol, thereby ensuring the safety of drug use. Within the concentration range investigated, the peak area and the detection concentration have a good linear relationship (r=1.000), the average recovery rate is in the range of 99% to 111%, the detection limit is 0.5ppm, and 25% of the maximum limit of 2ppm of ICHQ3C.

[0014] 2. In the prior art, the detection methods for benzene residues in drugs are all limit inspection methods. The present invention provides a method for determining benzene residues in acetone, toluene and ethanol recovered during drug production. It is the first time to conduct a quantitative inspection of benzene residues in acetone, toluene and ethanol, and can accurately determine the specific content of benzene residues in drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 This is the gas chromatogram of the blank solution in Experiment 1; Figure 2 This is the gas chromatogram of the control solution in Experiment 1; Figure 3 This is the gas chromatogram of the test solution in Experiment 1; Figure 4 This is the linear graph in Experiment 1; Figure 5 It is the gas chromatogram of Comparative Example 1; Figure 6 It is the gas chromatogram of Comparative Example 2; Figure 7 It is the gas chromatogram of Comparative Example 3; Figure 8 It is the gas chromatogram of Comparative Example 4; Fig. 9 It is the gas chromatogram of Comparative Example 5; Fig.10 This is the gas chromatogram of Comparative Example 6. DETAILED DESCRIPTION

[0016] Example 1 A method for determining residual benzene in acetone, toluene and ethanol recovered in the production process of acetone, toluene and ethanol solvents and tazobactam, characterized in that it comprises the following steps: S1. Prepare the test solution: take the test sample, place it in a gas phase injection vial, and seal it; S2. The test solution is detected by gas chromatography, wherein the chromatograph used in the gas chromatography is a capillary column gas chromatograph, and the chromatographic column of the capillary column gas chromatograph uses 5% phenyl dimethyl polysiloxane as the stationary liquid; the initial temperature of the chromatographic column is 40°C, maintained for 6 minutes, and then heated to 180°C at a rate of 60°C per minute and maintained for 10 minutes.

[0017] Moreover, the test samples are acetone, toluene and ethanol recovered during the production process of tazobactam.

[0018] Moreover, in the step S2, the chromatographic column of the capillary column gas chromatograph uses 5% phenyl dimethyl polysiloxane as the stationary liquid.

[0019] Moreover, the carrier gas of the capillary column gas chromatograph is nitrogen, and the flow rate of the carrier gas is 4 ml / min.

[0020] Moreover, the capillary column gas chromatograph adopts a hydrogen flame ionization detector.

[0021] Moreover, the injection mode of the gas chromatography method is split injection, and the injection volume is 0.8 μl.

[0022] Furthermore, the gas chromatography had an injection port temperature of 275°C and a detector temperature of 280°C.

[0023] Example 2 A method for determining residual benzene in acetone, toluene and ethanol recovered in the production process of acetone, toluene and ethanol solvents and tazobactam, characterized in that it comprises the following steps: S1. Prepare the test solution: take the test sample, place it in a gas phase injection vial, and seal it; S2. The test solution is detected by gas chromatography, wherein the chromatograph used in the gas chromatography is a capillary column gas chromatograph, and the chromatographic column of the capillary column gas chromatograph uses 5% phenyl dimethyl polysiloxane as the stationary liquid; the initial temperature of the chromatographic column is 40°C, maintained for 6 minutes, and then heated to 180°C at a rate of 60°C per minute and maintained for 10 minutes.

[0024] Moreover, the test sample is acetone recovered during the production process of amoxicillin.

[0025] Moreover, in the step S2, the chromatographic column of the capillary column gas chromatograph uses 5% phenyl dimethyl polysiloxane as the stationary liquid.

[0026] Moreover, the carrier gas of the capillary column gas chromatograph is nitrogen, and the flow rate of the carrier gas is 4 ml / min.

[0027] Moreover, the capillary column gas chromatograph adopts a hydrogen flame ionization detector.

[0028] Moreover, the injection mode of the gas chromatography method is split injection, and the injection volume is 0.8 μl.

[0029] Furthermore, the gas chromatography had an injection port temperature of 285°C and a detector temperature of 280°C.

[0030] Example 3 A method for determining residual benzene in acetone, toluene and ethanol recovered in the production process of acetone, toluene and ethanol solvents and tazobactam, characterized in that it comprises the following steps: S1. Prepare the test solution: take the test sample, place it in a gas phase injection vial, and seal it; S2. The test solution is detected by gas chromatography, wherein the chromatograph used in the gas chromatography is a capillary column gas chromatograph, and the chromatographic column of the capillary column gas chromatograph uses 5% phenyl dimethyl polysiloxane as the stationary liquid; the initial temperature of the chromatographic column is 40°C, maintained for 6 minutes, and then heated to 180°C at a rate of 60°C per minute and maintained for 10 minutes.

[0031] Moreover, the test samples are acetone and toluene recovered during the production process of potassium clavulanate.

[0032] Moreover, in the step S2, the chromatographic column of the capillary column gas chromatograph uses 5% phenyl dimethyl polysiloxane as the stationary liquid.

[0033] Moreover, the carrier gas of the capillary column gas chromatograph is nitrogen, and the flow rate of the carrier gas is 4 ml / min.

[0034] Moreover, the capillary column gas chromatograph adopts a hydrogen flame ionization detector.

[0035] Moreover, the injection mode of the gas chromatography method is split injection, and the injection volume is 0.8 μl.

[0036] Furthermore, the gas chromatography had an injection port temperature of 280°C and a detector temperature of 275°C.

[0037] Example 4 A method for determining residual benzene in acetone, toluene and ethanol recovered in the production process of acetone, toluene and ethanol solvents and tazobactam, characterized in that it comprises the following steps: S1. Prepare the test solution: take the test sample, place it in a gas phase injection vial, and seal it; S2. The test solution is detected by gas chromatography, wherein the chromatograph used in the gas chromatography is a capillary column gas chromatograph, and the chromatographic column of the capillary column gas chromatograph uses 5% phenyl dimethyl polysiloxane as the stationary liquid; the initial temperature of the chromatographic column is 40°C, maintained for 6 minutes, and then heated to 180°C at a rate of 60°C per minute and maintained for 10 minutes.

[0038] Moreover, the test samples are acetone, toluene and ethanol recovered during the production process of tazobactam.

[0039] Moreover, in the step S2, the chromatographic column of the capillary column gas chromatograph uses 5% phenyl dimethyl polysiloxane as the stationary liquid.

[0040] Moreover, the carrier gas of the capillary column gas chromatograph is nitrogen, and the flow rate of the carrier gas is 4 ml / min.

[0041] Moreover, the capillary column gas chromatograph adopts a hydrogen flame ionization detector.

[0042] Moreover, the injection mode of the gas chromatography method is split injection, and the injection volume is 0.8 μl.

[0043] Furthermore, the injection port temperature of the gas chromatography was 280°C and the detector temperature was 285°C.

[0044] Example 5 A method for determining residual benzene in acetone, toluene and ethanol recovered in the production process of acetone, toluene and ethanol solvents and tazobactam, characterized in that it comprises the following steps: S1. Prepare the test solution: take the test sample, place it in a gas phase injection vial, and seal it; S2. The test solution is detected by gas chromatography, wherein the chromatograph used in the gas chromatography is a capillary column gas chromatograph, and the chromatographic column of the capillary column gas chromatograph uses 5% phenyl dimethyl polysiloxane as the stationary liquid; the initial temperature of the chromatographic column is 40°C, maintained for 6 minutes, and then heated to 180°C at a rate of 60°C per minute and maintained for 10 minutes.

[0045] Moreover, the test samples are acetone, toluene and ethanol recovered during the production process of tazobactam.

[0046] Moreover, in the step S2, the chromatographic column of the capillary column gas chromatograph uses 5% phenyl dimethyl polysiloxane as the stationary liquid.

[0047] Moreover, the carrier gas of the capillary column gas chromatograph is nitrogen, and the flow rate of the carrier gas is 3.9 ml / min.

[0048] Moreover, the capillary column gas chromatograph adopts a hydrogen flame ionization detector.

[0049] Moreover, the injection mode of the gas chromatography method is split injection, and the injection volume is 0.8 μl.

[0050] Furthermore, the injection port temperature of the gas chromatography was 280°C and the detector temperature was 280°C.

[0051] Example 6 A method for determining residual benzene in acetone, toluene and ethanol recovered in the production process of acetone, toluene and ethanol solvents and tazobactam, characterized in that it comprises the following steps: S1. Prepare the test solution: take the test sample, place it in a gas phase injection vial, and seal it; S2, the test solution is detected by gas chromatography, the chromatograph used in the gas chromatography is a capillary column gas chromatograph, the chromatographic column of the capillary column gas chromatograph is 5% phenyl dimethyl polysiloxane was used as the stationary liquid; the initial temperature of the chromatographic column was 40°C, maintained for 6 minutes, and then heated to 180°C at a rate of 60°C per minute and maintained for 10 minutes.

[0052] Moreover, the test samples are acetone, toluene and ethanol recovered during the production process of tazobactam.

[0053] Moreover, in the step S2, the chromatographic column of the capillary column gas chromatograph uses 5% phenyl dimethyl polysiloxane as the stationary liquid.

[0054] Moreover, the carrier gas of the capillary column gas chromatograph is nitrogen, and the flow rate of the carrier gas is 4.1 ml / min.

[0055] Moreover, the capillary column gas chromatograph adopts a hydrogen flame ionization detector.

[0056] Moreover, the injection mode of the gas chromatography method is split injection, and the injection volume is 0.8 μl.

[0057] Furthermore, the injection port temperature of the gas chromatography was 280°C and the detector temperature was 280°C.

[0058] Example 7 A method for determining residual benzene in acetone, toluene and ethanol recovered in the production process of acetone, toluene and ethanol solvents and tazobactam, characterized in that it comprises the following steps: S1. Prepare the test solution: take the test sample, place it in a gas phase injection vial, and seal it; S2. The test solution is detected by gas chromatography, wherein the chromatograph used in the gas chromatography is a capillary column gas chromatograph, and the chromatographic column of the capillary column gas chromatograph uses 5% phenyl dimethyl polysiloxane as the stationary liquid; the initial temperature of the chromatographic column is 40°C, maintained for 6 minutes, and then heated to 180°C at a rate of 60°C per minute and maintained for 10 minutes.

[0059] Moreover, the test samples are acetone, toluene and ethanol recovered during the production process of tazobactam.

[0060] Moreover, in the step S2, the chromatographic column of the capillary column gas chromatograph uses 5% phenyl dimethyl polysiloxane as the stationary liquid.

[0061] Moreover, the carrier gas of the capillary column gas chromatograph is nitrogen, and the flow rate of the carrier gas is 4.0 ml / min.

[0062] Moreover, the capillary column gas chromatograph adopts a hydrogen flame ionization detector.

[0063] Moreover, the injection mode of the gas chromatography method is split injection, and the injection volume is 0.8 μl.

[0064] Furthermore, the injection port temperature of the gas chromatography was 280°C and the detector temperature was 280°C.

[0065] Comparative Example 1 Different from Example 7, in step S2, the initial temperature of the capillary column gas chromatograph is 40° C. and maintained for 30 min without further increasing the temperature.

[0066] Comparative Example 2 Different from Example 7, in step S2, the initial temperature of the capillary column gas chromatograph is 60° C. and maintained for 30 min without further increasing the temperature.

[0067] Comparative Example 3 Different from Example 7, the initial temperature of the capillary column gas chromatograph in step S2 is 100° C. and maintained for 30 min without further increasing the temperature.

[0068] Comparative Example 4 Different from Example 7, the initial temperature of the capillary column gas chromatograph in step S2 is 140° C. and maintained for 30 min without further increasing the temperature.

[0069] Comparative Example 5 Different from Example 7, the initial temperature of the capillary column gas chromatograph in step S2 is 180° C. and maintained for 30 min without further increasing the temperature.

[0070] Comparative Example 6 Different from Example 7, the initial temperature of the capillary column gas chromatograph in step S2 is 200° C. and maintained for 30 min without further heating.

[0071] Experimental Section

[0072] Experiment 1 1. Instrument and gas chromatography conditions instrument: Shimadzu GC-2010 gas chromatograph, Agilent CP-SiL 8 CB 50m×0.53mm×5.0μm chromatographic column, Mettler-Toledo XPR205DR electronic balance; Chromatographic conditions: Detector: FID; Flow rate: 4 ml / min; Split ratio: 30:1; Injection volume: 0.8 μl; Injection port temperature: 280 °C; Detector temperature: 280 °C; Column temperature: Initial temperature was 40°C, maintained for 6 minutes, then increased to 180°C at a rate of 60°C per minute and maintained for 10 minutes.

[0073] 2. Materials Benzene: AR grade, batch number S2772210001, provided by Tianjin Komiou Chemical Reagent Co., Ltd., content ≥99.5%; Methanol: AR grade, batch number S1242310007, provided by SIGMA, content ≥99.9%.

[0074] 3. Measurement of different test products Blank solution: methanol; Preparation of reference solution: take about 25 mg of benzene reference substance, accurately weigh it, put it in a 100 ml volumetric flask, dilute it to the mark with methanol, shake it well, accurately measure 5 ml, put it in a 50 ml volumetric flask, dilute it to the mark with methanol, shake it well, seal it, and you have it; Preparation of test solution: Take an appropriate amount of the test sample, place it in a gas phase vial and seal it.

[0075] Accurately measure 0.8 μL of each of the above solutions and inject them into the gas chromatograph, record the peak area, and measure the residual benzene content by the external standard method. The results are shown in Table 1.

[0076] Table 1 Benzene test results

[0077] In the table, M5: 3-methyl-[2-oxo-4-(2-benzothiazolyldisulfanyl)-1-azetidinyl]-3-butene diphenylmethyl ester), M7: deoxytazobactam diphenylmethyl ester, M9: tazobactam.

[0078] 4. Methodological Validation 4.1 Exclusivity The blank solution, control solution and test solution determined by the above method are shown in Table 1. Figure 1-Figure 3 , Figure 1 is the gas chromatogram of the blank solution. Figure 2 is the gas chromatogram of the reference solution. Figure 3 is the gas chromatogram of the test solution, Figure 3 The peaks in the sample were completely eluted, the baseline was stable, the detection repeatability was good, there were no interferents at the target peak position, and the test sample peak did not interfere with the determination of benzene.

[0079] 4.2 Linearity In the benzene concentration range of 1.53μg / ml-66.38μg / ml, the linear relationship is good. Figure 4 , linear equation: 499.6408X-218.3215, correlation coefficient: 1.000.

[0080] 4.3 Limit of detection and limit of quantification When the detection limit S / N≥3, LOD=0.5ppm, when the quantification limit S / N≥10, LOQ=1.5ppm.

[0081] 4.4 Precision Six samples from the same batch (M7 recovered acetone A) were measured in parallel and injected into the gas chromatograph respectively. The average content was 3ppm, RSD=0. At two different times, six test solutions were prepared in parallel using different instruments and injected into the gas chromatograph (n=12). The average result was 3ppm, RSD=10%.

[0082] Six samples from the same batch (M7 recovered acetone B) were measured in parallel and injected into the gas chromatograph respectively. The average content was not detected, the average value of the spiked results was 32ppm, and RSD=0. At two different times, six spiked solutions of the test sample were prepared in parallel using different instruments and injected into the gas chromatograph. The average result (n=12) was 32ppm, and RSD=1%.

[0083] Six samples from the same batch (M5 recovered toluene) were taken for parallel determination and injected into the gas chromatograph respectively. The average content was 22ppm, RSD=2%. At two different times, six test solutions were prepared in parallel using different instruments and injected into the gas chromatograph (n=12). The average result was 22ppm, RSD=3%.

[0084] Six samples from the same batch (M9 recovered ethanol) were measured in parallel and injected into the gas chromatograph respectively. The average content was not detected, and the average value of the spiked results was 6ppm, RSD=7%. At two different times, six spiked solutions of the test sample were prepared in parallel using different instruments and injected into the gas chromatograph. The average result (n=12) was 6ppm, RSD=9%.

[0085] 4.5 Accuracy According to the preparation method of the reference solution, take an appropriate amount of benzene and add M5 to recover toluene, M7 to recover acetone A, M7 to recover acetone B, and M9 to recover ethanol to dilute to make stock solutions containing approximately 0.43mg, 0.20mg, 0.205mg, and 0.044mg of benzene per 1ml. Take 1.6ml, 2ml, and 2.4ml of the above stock solutions and place them in 20ml volumetric flasks respectively. Prepare 3 portions in parallel for each concentration, inject them into the gas chromatograph, calculate the residual benzene content by the external standard method, and calculate the recovery rate.

[0086] Table 2 Results of recovery rate of toluene recovered by M5

[0087] Table 3 Results of recovery rate of acetone A recovered by M7

[0088] Table 4 Results of recovery rate of acetone B recovered by M7

[0089] Table 5 Results of M9 ethanol recovery rate

[0090] 4.6 Durability Three chromatographic columns of the same brand but different batches; when the flow rate changes by ±0.2ml / min; when the injection port temperature changes by ±5℃; when the detector temperature changes by ±5℃, benzene is detected in each recovered solvent; the correction factor of benzene in the reference solution is RSD≤1%, and the RSD of the benzene detection results in the recovered solvents is ≤1%, indicating good method durability.

[0091] Experiment 2 The recovered solvent was measured using the technical solution of Comparative Example 1, and the results are as follows Figure 5 As shown, from Figure 5 It can be seen that when the initial temperature was maintained at 40°C for 30 minutes, no benzene peak appeared and the control analysis was not completed.

[0092] The recovered solvent was measured using the technical solution of Comparative Example 2, and the results are as follows Figure 6 As shown, from Figure 6 It can be seen that the initial temperature of the chromatographic column is 60°C and maintained for 30 minutes, and benzene peaks appear, indicating that the above technical solution is feasible, but the peak response is low and does not meet the limit requirement of 0.2ppm.

[0093] The recovered solvent was measured using the technical solution of Comparative Example 3, and the results are as follows Figure 7 As shown, from Figure 7It can be seen that the initial temperature is 100℃ and maintained for 30min; benzene peak is detected and the response value increases.

[0094] The recovered solvent was measured using the technical solution of Comparative Example 4, and the results are as follows Figure 8 As shown, from Figure 8 It can be seen that the initial temperature is 140°C and maintained for 30 minutes; benzene peaks are detected, and the response value increases compared with Comparative Example 3.

[0095] The recovered solvent was measured using the technical solution of Comparative Example 5, and the results are as follows Fig. 9 As shown, from Fig. 9 It can be seen that the initial temperature is 180°C and maintained for 30 minutes; benzene peaks are detected, and the response value increases compared with Comparative Example 4.

[0096] The recovered solvent was measured using the technical solution of Comparative Example 6, and the results are as follows Fig.10 As shown, from Fig.10 It can be seen that the initial temperature is 200°C and maintained for 30 minutes; benzene peaks are detected, and the response value increases compared with Comparative Example 5.

[0097] By comparing Examples 1-6 ( Figure 5-10 ) and Experiment 1 ( Figure 3 ) shows that with the increase of temperature, the response value of benzene increases from 250mv to 1750mv. While meeting the detection requirements, considering the interference of other peaks in the sample on the target, the final gradient temperature of 180℃ is selected.

[0098] The above experimental results can prove that the gradient heating technical solution of the present invention can effectively detect the benzene residue in the recovered solvent, and temperature changes will affect the benzene residue detection.

Claims

1. A method for determining residual benzene in acetone, toluene and ethanol recovered during drug production, characterized in that: The steps include: S1. Prepare the test solution: take the test sample, put it into a gas phase injection vial, obtain the test solution, and seal it; S2. The test solution is detected by gas chromatography, and the chromatograph used in the gas chromatography is a capillary column gas chromatograph. The initial temperature of the chromatographic column of the capillary column gas chromatograph is 40°C, which is maintained for 6 minutes, and then the temperature is increased to 180°C at a rate of 60°C per minute and maintained for 10 minutes.

2. The method for determining the residual benzene in acetone, toluene and ethanol recovered in a drug production process as claimed in claim 1, characterized in that: The test samples are acetone, toluene and ethanol reagents.

3. The method for determining the residual benzene in acetone, toluene and ethanol recovered in a drug production process as claimed in claim 1, characterized in that: The test samples are acetone, toluene and ethanol recovered during the production process of tazobactam.

4. The method for determining the residual benzene in acetone, toluene and ethanol recovered in a drug production process as claimed in claim 1, characterized in that: The test sample is acetone recovered during the production process of amoxicillin.

5. The method for determining the residual benzene in acetone, toluene and ethanol recovered in a drug production process as claimed in claim 1, characterized in that: The test samples are acetone and toluene recovered during the production process of potassium clavulanate.

6. The method for determining the residual benzene in acetone, toluene and ethanol recovered in a drug production process as claimed in claim 1, characterized in that: In step S2, the chromatographic column of the capillary column gas chromatograph uses 5% phenyl dimethyl polysiloxane as the stationary liquid.

7. The method for determining the residual benzene in acetone, toluene and ethanol recovered in a drug production process as claimed in claim 1, characterized in that: In step S2, the carrier gas of the capillary column gas chromatograph is nitrogen, and the flow rate of the carrier gas is 3.9-4.1 ml / min.

8. The method for determining the residual benzene in acetone, toluene and ethanol recovered in a drug production process as claimed in claim 1, characterized in that: The capillary column gas chromatograph adopts a hydrogen flame ionization detector.

9. The method for determining the residual benzene in acetone, toluene and ethanol recovered in a drug production process as claimed in claim 1, characterized in that: The injection mode of the gas chromatography method is split injection, and the injection volume is 0.8 μl.

10. The method for determining the residual benzene in acetone, toluene and ethanol recovered in a drug production process according to claim 1, characterized in that: The injection port temperature of the gas chromatography is 275°C-285°C, and the detector temperature is 275°C-285°C.

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