Method for detecting content of semi-volatile unknown substances in leach liquor of C-type persistent contact medical apparatus and instruments

Abstract

The invention discloses a method for detecting the content of a semi-volatile unknown substance in a leaching solution of a C-type persistent contact medical device. According to the method disclosed by the invention, the content of the non-volatile unknown substances in the extract liquid of the C-type persistent contact medical equipment is determined by quantifying or semi-quantifying the non-volatile unknown substances in the extract liquid of the C-type persistent contact medical equipment and adopting a gas chromatograph-mass spectrometer; and performing qualitative and quantitative analysis on the semi-volatile organic compounds in the leaching liquor by adopting a mode of combining an NIST database with artificial spectrum unfolding. According to the method, strict experimental design and verification processes are adopted, so that the accuracy and reliability of detection of the non-volatile unknown substances in the medical instrument leach liquor are ensured, and meanwhile, the conditions of qualitative inaccuracy and analysis omission of the non-volatile unknown substances in the C-class persistent contact medical instrument leach liquor are also avoided.

Description

Technical Field

[0001] The present invention belongs to the technical field of medical device detection, and in particular relates to a method for detecting the content of semi-volatile unknown substances in an extract of a Class C permanent contact medical device. Background Art

[0002] With the continuous development of medical technology, the use of Class C persistent contact medical devices in clinical processes has gradually increased. However, Class C medical devices are persistent contact devices. During clinical use, they continuously contact with the human body and release substances. Leachable substances may cause safety hazards to the human body in the short or long term. Therefore, it is necessary to strengthen the research on leachable substances of Class C persistent contact medical devices. Leachable substances are substances released by medical devices when they are in continuous contact with the human body during clinical use. Extractable substances are substances that can be released when medical devices are extracted with extraction solvents or under conditions at least the same as or more stringent than the expected use. The released chemical substances generally include sterilization residual agents, processing residues, degradation products, monomers and additives in materials, etc.

[0003] However, the accuracy and reliability of non-volatile unknowns in the common research on leachable substances are not high enough. At the same time, the qualitative analysis of semi-volatile unknowns in the extracts of Class C persistent contact medical devices is prone to inaccuracies and analytical omissions. Summary of the invention

[0004] The object of the present invention is to provide a method for detecting the content of semi-volatile unknown substances in the extract of Class C permanent contact medical devices in order to solve the above-mentioned problems.

[0005] The technical solution adopted by the present invention is as follows: a method for detecting the content of semi-volatile unknown substances in the extract of Class C permanent contact medical devices, characterized in that the method comprises the following steps:

[0006] S1. Prepare 12 kinds of semi-volatile organic compound mixed standard working solutions, quantitative limit solutions, accuracy solutions and di-n-butyl phthalate-D4 internal standard solutions; the concentration range of the mixed standard working solutions is set to 0.10μg / mL to 1.0μg / mL, the quantitative limit solution is a 0.10μg / mL mixed standard working solution, the accuracy solution is a mixed standard working solution of three concentrations: low, medium and high, and the concentration of the di-n-butyl phthalate-D4 internal standard solution is set to 10μg / mL;

[0007] S2. Use gas chromatography-mass spectrometry to analyze the series of mixed standard working solutions, quantitative limit solutions, accuracy solutions and di-n-butyl phthalate-D4 internal standard solutions respectively; perform linear regression analysis on the series of mixed standard working solutions to obtain a linear regression equation and establish a calibration curve; repeat the injection of the quantitative limit solution for 3 injections for analysis and calculate the signal-to-noise ratio; analyze the mixed standard working solutions of low, medium and high concentrations to obtain accuracy (repeatability) results; analyze the concentration and peak area, characteristic ions and retention time of the di-n-butyl phthalate-D4 internal standard solution;

[0008] S3. The samples were placed in polytetrafluoroethylene bottles, and physiological saline, ethanol, and n-hexane extraction solutions were added. After sealing, the bottles were shaken and extracted in a full-temperature shaking incubator to obtain sample extracts. Similarly, the extracts without adding samples were used as blank extracts.

[0009] S4. Pipette 10 mL of the saline sample extract and the saline blank extract extracted in step S3 into a separatory funnel, add the di-n-butyl phthalate-D4 internal standard solution prepared in step S1, and then extract twice with dichloromethane. Combine the organic phases, concentrate and fix the volume with nitrogen, and then vortex to obtain the test solution;

[0010] S5. The ethanol extract and the n-hexane extract obtained in step S3 are respectively transferred to a nitrogen blowpipe, and the di-n-butyl phthalate-D4 internal standard solution prepared in step S1 is added, and the solution is concentrated and fixed to volume by nitrogen blowpipe and vortexed to obtain the test solution;

[0011] S6. The test liquid is measured by gas chromatography-mass spectrometry to perform qualitative and / or quantitative analysis on the semi-volatile unknown substances in the test liquid; this method has high accuracy, good linearity, low quantitative limit, good repeatability and easy operation.

[0012] In a preferred embodiment, in step S1, the 12 semi-volatile organic compounds include compounds such as aldehydes, esters, phenols, acids, aldehydes, etc., the concentration range of the mixed standard working solution is set to 0.10 μg / mL, 0.20 μg / mL, 0.40 μg / mL, 0.60 μg / mL, and 1.0 μg / mL, the quantitative limit solution is a 0.10 μg / mL mixed standard working solution, the accuracy solution is a mixed standard working solution with concentrations of 0.20 μg / mL, 0.40 μg / mL, and 0.80 μg / mL, and the concentration of the di-n-butyl phthalate-D4 internal standard solution is set to 10 μg / mL.

[0013] In a preferred embodiment, the step S2 uses a gas chromatography-mass spectrometer to respectively analyze the series of mixed standard working solutions, the quantitative limit solution, the accuracy solution and the di-n-butyl phthalate-D4 internal standard solution; the series of mixed standard working solutions are subjected to linear regression analysis to obtain a linear regression equation and establish a calibration curve; the quantitative limit solution is repeatedly injected 3 times for analysis and the signal-to-noise ratio is calculated; the mixed standard working solutions with concentrations of 0.20 μg / mL, 0.40 μg / mL, and 0.80 μg / mL are analyzed, and these three concentration accuracy solutions are added to a blank extract, and the sample extract is treated in accordance with the pre-treatment method to obtain the accuracy (repeatability) result; the concentration, peak area and retention time of the di-n-butyl phthalate-D4 internal standard solution as the internal standard substance are analyzed.

[0014] In a preferred embodiment, in step S3, the sample is placed in a polytetrafluoroethylene bottle, the extraction solution is physiological saline, ethanol, and n-hexane solvent, and after the bottle cap is rotated to seal, the sample is shaken and extracted at a rate of 60 r / min in a 37°C full-temperature shaking incubator.

[0015] In a preferred embodiment, in step S4, the upper and lower pistons of the separating funnel are both made of polytetrafluoroethylene, the nitrogen blowpipe has a capacity of 20 mL, and a graduation of 0.1 mL.

[0016] In a preferred embodiment, in step S4, the physiological saline extract pretreatment step is: ① adding 10 mL of sample extract to a 60 mL separatory funnel, and adding 10 mL of blank extract to a 60 mL separatory funnel; ② adding di-n-butyl phthalate-D4 internal standard solution to the blank extract and the sample extract, and then adding 10 mL of dichloromethane, holding the separatory funnel, shaking to release gas, and shaking for 5 minutes for extraction; ③ the separatory funnel is left to stand on the iron stand for 10 to 20 minutes, the dichloromethane layer is transferred to a 20 mL nitrogen blowpipe, and then 10 mL of dichloromethane is added to the aqueous phase for a second extraction, and the two organic phases are combined; ④ under heating conditions at 40° C., the organic phase is concentrated by nitrogen blowing, the nitrogen is turned on until there is airflow fluctuation on the surface of the solvent, and the nitrogen blowpipe wall is washed with dichloromethane several times. When it is concentrated to 0.5 mL, it is fixed to volume with dichloromethane and vortexed for 0.5 minutes to obtain a test solution.

[0017] In a preferred embodiment, in step S4, the ethanol extract pretreatment step is: ① adding 10 mL of ethanol sample extract to a 20 mL nitrogen blowpipe, and adding 10 mL of ethanol blank extract and ethanol blank extract to a 20 mL nitrogen blowpipe; ② adding di-n-butyl phthalate-D4 internal standard solution to the blank extract and the sample extract; ③ nitrogen blowing and concentrating under heating conditions at 40° C., turning on the nitrogen until there is airflow fluctuation on the surface of the solvent, washing the nitrogen blowpipe wall with dichloromethane several times, and when concentrated to 0.5 mL, vortexing for 0.5 min after constant volume with dichloromethane to obtain a test solution.

[0018] In a preferred embodiment, in step S4, the n-hexane extract pretreatment step is the same as the ethanol extract pretreatment step.

[0019] In a preferred embodiment, in step S6, the chromatographic conditions of the gas chromatography-mass spectrometer are:

[0020] Flow rate: 1mL / min; chromatographic column: HP-5MS UI, 30m×250μm×0.25μm; heating program: starting temperature 60℃, hold for 3min, increase to 220℃ at a rate of 20℃ / min, hold for 1min, increase to 300℃ at a rate of 10℃ / min, hold for 10min; injection port temperature: 280℃; injection volume: 1μL; split mode: non-split; carrier gas: He; mass spectrometer transmission line temperature: 300℃.

[0021] In a preferred embodiment, in step S6, the mass spectrometry conditions of the gas chromatography-mass spectrometer are: ion source: EI; ion source temperature: 230°C; quadrupole temperature: 150°C; solvent delay time: 3 min; scanning mode and range: SCAN / SIM; range: 29-550 m / z.

[0022] In summary, due to the adoption of the above technical solution, the beneficial effects of the present invention are:

[0023] 1. In the present invention, the non-volatile unknown substances in the extract of Class C persistent contact medical devices are quantitatively or semi-quantitatively determined by using a gas chromatography-mass spectrometer to determine the content of the non-volatile unknown substances in the extract of Class C persistent contact medical devices, and the semi-volatile organic substances in the extract are qualitatively and quantitatively analyzed by using the NIST database combined with manual spectrum interpretation.

[0024] 2. In the present invention, a strict experimental design and verification process is adopted to ensure the accuracy and reliability of the detection of non-volatile unknown substances in the medical device extract, while also avoiding the inaccurate qualitative analysis and analytical omissions of semi-volatile unknown substances in the Class C persistent contact medical device extract.

[0025] 3. In the present invention, quantitative analysis is performed on organic substances whose retention time and fragmentation information are consistent with those of existing standards, and semi-quantitative analysis is performed on organic substances for which there is no standard for quantification. Finally, all semi-volatile organic substances released by Class C persistent contact medical devices that are higher than the analysis threshold AET (analysis threshold) are analyzed, thereby improving the accuracy, reliability and comprehensiveness of the detection of non-volatile unknown substances in the extract of Class C persistent contact medical devices. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 It is the total ion current (TIC) gas chromatogram of 12 semi-volatile organic compounds in the embodiment of the present invention;

[0027] Figure 2 It is a total ion current (TIC) gas chromatogram of di-n-butyl phthalate-D4 internal standard solution in an embodiment of the present invention;

[0028] Figure 3 This is a full scan mass spectrum of the internal standard solution of di-n-butyl phthalate-D4 in the embodiment of the present invention;

[0029] Figure 4 Schematic diagram of the calibration curve of nonanal in an embodiment of the present invention;

[0030] Figure 5 Schematic diagram of the calibration curve of caprolactam in an embodiment of the present invention;

[0031] Figure 6 Schematic diagram of the calibration curve of diethylene glycol butyl ether acetate in an embodiment of the present invention;

[0032] Figure 7 Schematic diagram of the calibration curve of 2-hydroxyethyl benzoate in an embodiment of the present invention;

[0033] Figure 8 Schematic diagram of the calibration curve of 2,6-di-tert-butylphenol in an embodiment of the present invention;

[0034] Fig. 9 Schematic diagram of the calibration curve of tetradecamethylcycloheptasiloxane in an embodiment of the present invention;

[0035] Fig.10 Schematic diagram of the calibration curve of 2,4-di-tert-butylphenol in an embodiment of the present invention;

[0036] Fig.11 Schematic diagram of the calibration curve of diisobutyl phthalate in an embodiment of the present invention;

[0037] Fig.12 Schematic diagram of the calibration curve of methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate in the embodiment of the present invention;

[0038] Fig.13 Schematic diagram of the calibration curve of dibutyl phthalate in an embodiment of the present invention;

[0039] Fig.14 Schematic diagram of the calibration curve of di(2-ethylhexyl) maleate in the embodiment of the present invention;

[0040] Fig.15 Schematic diagram of the calibration curve of trioctyl trimellitate in an embodiment of the present invention;

[0041] Fig.16 The total ion current (TIC) gas chromatogram of the blank extract of physiological saline in the embodiment of the present invention;

[0042] Fig.17 It is a total ion current (TIC) gas chromatogram of the physiological saline sample extract 1 in an embodiment of the present invention;

[0043] Fig.18 It is a total ion current (TIC) gas chromatogram of the physiological saline sample extract 2 in an embodiment of the present invention;

[0044] Fig.19 It is the total ion current (TIC) gas chromatogram of the ethanol blank extract in the embodiment of the present invention;

[0045] Fig. 20 It is a total ion current (TIC) gas chromatogram of the ethanol sample extract 1 in the embodiment of the present invention;

[0046] Fig.21 It is a total ion current (TIC) gas chromatogram of the ethanol sample extract 2 in the embodiment of the present invention;

[0047] Fig. 22 It is the total ion current (TIC) gas chromatogram of the n-hexane blank extract in the embodiment of the present invention;

[0048] Fig.23 This is a total ion current (TIC) gas chromatogram of the n-hexane sample extract 1 in an embodiment of the present invention;

[0049] Fig.24 This is a total ion current (TIC) gas chromatogram of the n-hexane sample extract 2 in an embodiment of the present invention;

[0050] Fig.25 This is the mass spectrum of the unknown substance determined at 21.46 min of the ethanol sample extract in the embodiment of the present invention;

[0051] Fig.26 is the mass spectrum of caprolactam under the conditions of the present invention;

[0052] Fig. 27 It is a calibration curve diagram of caprolactam under the conditions of the present invention;

[0053] Fig.28 The mass spectrum of the unknown substance determined at 16.58 min of the n-hexane sample extract in the embodiment of the present invention;

[0054] Fig.29 is the mass spectrum of dichloroparaxylene dimer under the conditions of the present invention;

[0055] Fig.30 It is a calibration curve diagram of dichloroparaxylene dimer under the conditions of the present invention;

[0056] Fig.31 This is the mass spectrum of the possible unknown substance at 16.40 min of the n-hexane sample extract in the embodiment of the present invention;

[0057] Fig.32 This is the mass spectrum of (1,1-dichloroethyl)benzene under the conditions of the present invention. DETAILED DESCRIPTION

[0058] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0059] Reference Figure 1-32 ,

[0060] Example:

[0061] This example uses a Class C permanent contact medical device occluder to detect semi-volatile unknown substances in the occluder extract, and the steps are as follows:

[0062] 1. Prepare solutions: prepare 12 semi-volatile organic compound standards in Table 1 into 10 μg / mL mixed standard stock solutions, and then prepare a series of mixed standard working solutions with a concentration range of 0.10 μg / mL, 0.20 μg / mL, 0.40 μg / mL, 0.60 μg / mL, and 1.0 μg / mL; prepare a mixed standard working solution with a concentration of 0.10 μg / mL as the quantitative limit solution; prepare mixed standard working solutions with concentrations of 0.20 μg / mL, 0.40 μg / mL, and 0.80 μg / mL as the accuracy solution; prepare a 10 μg / mL internal standard solution of di-n-butyl phthalate-D4.

[0063] Table 112 names and CAS numbers of semi-volatile organic compounds

[0064]

[0065]

[0066] 2. Method validation: Use gas chromatography-mass spectrometry to analyze the series of mixed standard working solutions, quantitative limit solutions, accuracy solutions and di-n-butyl phthalate-D4 internal standard solutions. Perform linear regression analysis on the series of mixed standard working solutions to obtain a linear regression equation and establish a calibration curve. The calibration curve is shown in Figures 4 to 16 , the linear regression equation is shown in Table 2; the quantitative limit solution was repeatedly injected 3 times for analysis, the signal-to-noise ratio was calculated, and the quantitative limit results are shown in Table 3; the mixed standard working solutions with concentrations of 0.20μg / mL, 0.40μg / mL, and 0.80μg / mL were analyzed, and these three concentration accuracy solutions were added to the blank extract, and the same sample pretreatment method was used for treatment. The accuracy (repeatability) results are shown in Table 4; the concentration and peak area, characteristic ions and retention time of the internal standard solution of di-n-butyl phthalate-D4 as the internal standard substance were analyzed, and the chromatogram results are shown in Figure 2 , mass spectrum results are shown in Figure 3 .

[0067] Table 2 Linearity results

[0068]

[0069]

[0070] Table 3 Quantitation limit / S / N ratio results

[0071]

[0072] Table 4 Accuracy (repeatability) results

[0073]

[0074] 3. Sample processing: Place the sample in a polytetrafluoroethylene bottle, add physiological saline, ethanol, and n-hexane extraction solution, rotate the bottle cap to seal it, and then oscillate it in a 37°C full-temperature shaking incubator at a rate of 60 r / min for 72 hours to obtain the extract.

[0075] 4. Extraction liquid treatment:

[0076] 4.1 The pretreatment steps of the physiological saline extract are as follows: ① Add 10 mL of sample extract to two 60 mL separatory funnels respectively, and add 10 mL of blank extract to one 60 mL separatory funnel; ② Add 100 μL of di-n-butyl phthalate-D4 internal standard solution to the sample extract and the blank extract, and then add 10 mL of dichloromethane, hold the separatory funnel, shake to release gas, and shake for 5 minutes to extract; ③ The separatory funnel is placed on an iron stand for 10 to 20 minutes, the dichloromethane layer is transferred to a 20 mL nitrogen blowpipe, and 10 mL of dichloromethane is added to the aqueous phase for a second extraction, and the two organic phases are combined; ④ Under heating conditions of 40°C, the organic phase is concentrated by nitrogen blowpipe, the nitrogen is turned on until there is airflow fluctuation on the surface of the solvent, and the wall of the nitrogen blowpipe is washed with dichloromethane for multiple times. When it is concentrated to 0.5 mL, it is fixed to 1 mL with dichloromethane, and vortexed for 0.5 minutes to obtain the test solution.

[0077] 4.2 The pretreatment steps of the ethanol extract are as follows: ① Add 10 mL of ethanol sample extract to two 20 mL nitrogen blowpipes respectively, and add 10 mL of ethanol blank extract to one 20 mL nitrogen blowpipe; ② Add 100 μL of di-n-butyl phthalate-D4 internal standard solution to the sample extract and the blank extract; ③ Concentrate with nitrogen blowpipe under heating conditions at 40 °C, turn on the nitrogen until there is airflow fluctuation on the surface of the solvent, wash the nitrogen blowpipe wall with dichloromethane several times, and when it is concentrated to 0.5 mL, make up to 1 mL with dichloromethane, vortex for 0.5 min, and obtain the test solution.

[0078] 4.3 The pretreatment steps of the n-hexane extract are the same as those of the ethanol extract.

[0079] 5. Take the test liquid for machine detection: Use gas chromatography-mass spectrometry to measure the test liquid, first use full scan mode (TIC) to perform qualitative analysis on the semi-volatile organic compounds in the test liquid, and the detected compounds are identified as much as possible by reference to the database or manual spectrum interpretation. Then establish a SIM method, use the SIM scan mode to detect and analyze the test liquid, and finally perform quantitative analysis and / or semi-quantitative analysis on the identified substances.

[0080] The chromatographic conditions of the gas chromatography-mass spectrometry were:

[0081] Flow rate: 1mL / min; chromatographic column: HP-5MS UI, 30m×250μm×0.25μm; heating program: starting temperature 60℃, hold for 3min, increase to 220℃ at a rate of 20℃ / min, hold for 1min, increase to 300℃ at a rate of 10℃ / min, hold for 10min; injection port temperature: 280℃; injection volume: 1μL; split mode: non-split; carrier gas: He; mass spectrometer transmission line temperature: 300℃.

[0082] The mass spectrometry conditions of the gas chromatography-mass spectrometry instrument are:

[0083] Ion source: EI; ion source temperature: 230°C; quadrupole temperature: 150°C; solvent delay time: 3 min; scanning mode and range: SCAN / SIM; range: 29-550 m / z.

[0084] 6. Analysis of internal standard recovery rate: The recovery rate is required to be between 80% and 115%. As shown in Table 5, the recovery rate results meet the requirements.

[0085] Table 5 Internal standard recovery results

[0086]

[0087] 7. Identification and analysis results of unknown substances

[0088] 7.1 Qualitative analysis of the unknown substance at 21.46 min of the ethanol sample extract was performed. The mass spectrum of the unknown substance is shown in Fig.25 The unknown substance was determined to be erucamide. The mass spectrum is shown in Fig.26 .

[0089] 7.2 Calibration curve of erucamide is shown in Fig. 27 , the erucamide in the ethanol sample extract was quantitatively analyzed by the external standard method.

[0090] 7.3 Qualitative analysis of the unknown substance at 16.58 min of the n-hexane sample extract was performed. The mass spectrum of the unknown substance is shown in Fig.28 The unknown substance was determined to be dichloro-p-xylene dimer. The mass spectrum is shown in Fig.29 .

[0091] 7.4 Calibration curve of dichloroparaxylene dimer is shown in Fig.30 , the dichloroparaxylene dimer in the n-hexane sample extract was quantitatively analyzed by the external standard method.

[0092] 7.5 Qualitative analysis of the unknown substance at 16.40 min of the n-hexane sample extract was performed. The mass spectrum of the unknown substance is shown in Fig.31 The unknown substance may be (1,1-dichloroethyl)benzene. The mass spectrum is shown in Fig.32 The peak area of ​​10 μg / mL dichloroparaxylene dimer standard substance was used as reference for conversion and semi-quantitative analysis was performed.

[0093] Table 6 Quantitative results of the extract

[0094]

[0095] From the above, it can be seen that the present invention can complete the quantitative or semi-quantitative detection of non-volatile unknown substances in the extract of Class C persistent contact medical devices, and adopts a strict experimental design and verification process to ensure the accuracy and reliability of the detection of non-volatile unknown substances in the extract of Class C persistent contact medical devices, while also avoiding the inaccurate qualitative detection and analytical omissions of semi-volatile unknown substances in the extract of Class C persistent contact medical devices.

[0096] In the present invention, the organic matter whose retention time and fragmentation information are consistent with those of the existing standard is quantitatively analyzed, the organic matter without standard quantitative analysis is semi-quantitatively analyzed, and finally all the semi-volatile organic matter released by the Class C persistent contact medical device above the analysis threshold AET (analysis threshold) is analyzed, thereby improving the accuracy, reliability and comprehensiveness of the detection of non-volatile unknown substances in the extract of the Class C persistent contact medical device.

[0097] It should be noted that, in this article, relational terms such as first and second, etc. are only used to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Moreover, the terms "include", "comprise" or any other variants thereof are intended to cover non-exclusive inclusion, so that a process, method, article or device including a series of elements includes not only those elements, but also other elements not explicitly listed, or also includes elements inherent to such process, method, article or device. In the absence of further restrictions, the elements defined by the sentence "comprise a ..." do not exclude the existence of other identical elements in the process, method, article or device including the elements.

[0098] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit the same. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that the technical solutions described in the aforementioned embodiments may still be modified, or some of the technical features may be replaced by equivalents. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for detecting the content of semi-volatile unknown substances in the extract of Class C permanent contact medical devices, characterized in that: The method comprises the following steps: S1. Prepare 12 kinds of semi-volatile organic compound mixed standard working solutions, quantitative limit solutions, accuracy solutions and di-n-butyl phthalate-D4 internal standard solutions; the concentration range of the mixed standard working solutions is set to 0.10μg / mL to 1.0μg / mL, the quantitative limit solution is a 0.10μg / mL mixed standard working solution, the accuracy solution is a mixed standard working solution of three concentrations: low, medium and high, and the concentration of the di-n-butyl phthalate-D4 internal standard solution is set to 10μg / mL; S2. Use gas chromatography-mass spectrometry to analyze the series of mixed standard working solutions, quantitative limit solutions, accuracy solutions and di-n-butyl phthalate-D4 internal standard solutions respectively; perform linear regression analysis on the series of mixed standard working solutions to obtain a linear regression equation and establish a calibration curve; repeat the quantitative limit solution for 3 injections for analysis and calculate the signal-to-noise ratio; analyze the mixed standard working solutions of low, medium and high concentrations to obtain accuracy results; analyze the concentration and peak area, characteristic ions and retention time of the di-n-butyl phthalate-D4 internal standard solution; S3. The samples were placed in polytetrafluoroethylene bottles, and physiological saline, ethanol, and n-hexane extraction solutions were added. After sealing, the bottles were shaken and extracted in a full-temperature shaking incubator to obtain sample extracts. Similarly, the extracts without adding samples were used as blank extracts. S4. Pipette 10 mL of the saline sample extract and the saline blank extract extracted in step S3 into a separatory funnel, add the di-n-butyl phthalate-D4 internal standard solution prepared in step S1, and then extract twice with dichloromethane. Combine the organic phases, concentrate and fix the volume with nitrogen, and then vortex to obtain the test solution; S5. The ethanol extract and the n-hexane extract obtained in step S3 are respectively transferred to a nitrogen blowpipe, and the di-n-butyl phthalate-D4 internal standard solution prepared in step S1 is added, and the solution is concentrated and fixed to volume by nitrogen blowpipe and vortexed to obtain the test solution; S6. The test liquid is measured by gas chromatography-mass spectrometry to perform qualitative and / or quantitative analysis on the semi-volatile unknown substances in the test liquid; this method has high accuracy, good linearity, low quantitative limit, good repeatability and easy operation.

2. The method for detecting the content of semi-volatile unknown substances in the extract of a Class C permanent contact medical device according to claim 1, characterized in that: In step S1, the 12 semi-volatile organic compounds include compounds such as aldehydes, esters, phenols, acids, aldehydes, etc. The concentration range of the mixed standard working solution is set to 0.10 μg / mL, 0.20 μg / mL, 0.40 μg / mL, 0.60 μg / mL, and 1.0 μg / mL. The quantitative limit solution is a 0.10 μg / mL mixed standard working solution. The accuracy solution is a mixed standard working solution with concentrations of 0.20 μg / mL, 0.40 μg / mL, and 0.80 μg / mL. The concentration of the di-n-butyl phthalate-D4 internal standard solution is set to 10 μg / mL.

3. The method for detecting the content of semi-volatile unknown substances in the extract of a Class C permanent contact medical device according to claim 1, characterized in that: The step S2 uses a gas chromatography-mass spectrometer to respectively analyze the series of mixed standard working solutions, the quantitative limit solution, the accuracy solution and the di-n-butyl phthalate-D4 internal standard solution; the series of mixed standard working solutions are subjected to linear regression analysis to obtain a linear regression equation and establish a calibration curve; the quantitative limit solution is repeatedly sampled 3 times for analysis and the signal-to-noise ratio is calculated; the mixed standard working solutions with concentrations of 0.20 μg / mL, 0.40 μg / mL and 0.80 μg / mL are analyzed, and these three concentration accuracy solutions are added to a blank extract, and the sample extract is treated in accordance with the pre-treatment method to obtain the accuracy result; the concentration, peak area and retention time of the di-n-butyl phthalate-D4 internal standard solution as the internal standard substance are analyzed.

4. The method for detecting the content of semi-volatile unknown substances in the extract of a Class C permanent contact medical device according to claim 1, characterized in that: In step S3, the sample is placed in a polytetrafluoroethylene bottle, the extraction solution is physiological saline, ethanol, and n-hexane solvent, and after the bottle cap is rotated to seal, it is shaken and extracted at a rate of 60 r / min in a 37° C. full-temperature shaking incubator.

5. The method for detecting the content of semi-volatile unknown substances in the extract of a Class C permanent contact medical device according to claim 1, characterized in that: In step S4, the upper and lower pistons of the separating funnel are both made of polytetrafluoroethylene, the nitrogen blowpipe has a capacity of 20 mL and a graduation of 0.1 mL.

6. The method for detecting the content of semi-volatile unknown substances in the extract of a Class C permanent contact medical device according to claim 1, characterized in that: In the step S4, the pretreatment steps of the physiological saline extract are as follows: ① adding 10 mL of sample extract to a 60 mL separatory funnel, and adding 10 mL of blank extract to a 60 mL separatory funnel; ② adding di-n-butyl phthalate-D4 internal standard solution to the blank extract and the sample extract, and then adding 10 mL of dichloromethane, holding the separatory funnel, shaking to release gas, and shaking for 5 minutes to extract; ③ the separatory funnel is left to stand on an iron stand for 10 to 20 minutes, the dichloromethane layer is transferred to a 20 mL nitrogen blowpipe, and then 10 mL of dichloromethane is added to the aqueous phase for a second extraction, and the two organic phases are combined; ④ under heating conditions of 40° C., the organic phase is concentrated by nitrogen blowing, the nitrogen is turned on until there is airflow fluctuation on the surface of the solvent, and the nitrogen blowpipe wall is washed with dichloromethane for multiple times. When it is concentrated to 0.5 mL, it is fixed to volume with dichloromethane and vortexed for 0.5 minutes to obtain a test solution.

7. The method for detecting the content of semi-volatile unknown substances in the extract of a Class C permanent contact medical device according to claim 1, characterized in that: In the step S4, the ethanol extract pretreatment steps are: ① adding 10 mL of ethanol sample extract to a 20 mL nitrogen blowpipe, and adding 10 mL of ethanol blank extract and ethanol blank extract to a 20 mL nitrogen blowpipe; ② adding di-n-butyl phthalate-D4 internal standard solution to the blank extract and the sample extract; ③ nitrogen blowing and concentrating under heating conditions at 40° C., turning on the nitrogen until there is air flow fluctuation on the surface of the solvent, washing the nitrogen blowpipe wall with dichloromethane for multiple times, and when concentrated to 0.5 mL, constant volume with dichloromethane and vortexing for 0.5 min to obtain a test solution.

8. The method for detecting the content of semi-volatile unknown substances in the extract of a Class C permanent contact medical device according to claim 1, characterized in that: In step S4, the pretreatment step of the n-hexane extract is the same as the pretreatment step of the ethanol extract.

9. The method for detecting the content of semi-volatile unknown substances in the extract of a Class C permanent contact medical device according to claim 1, characterized in that: In step S6, the chromatographic conditions of the gas chromatography-mass spectrometer are: Flow rate: 1mL / min; chromatographic column: HP-5MS UI, 30m×250μm×0.25μm; heating program: starting temperature 60℃, hold for 3min, increase to 220℃ at a rate of 20℃ / min, hold for 1min, increase to 300℃ at a rate of 10℃ / min, hold for 10min; injection port temperature: 280℃; injection volume: 1μL; split mode: non-split; carrier gas: He; mass spectrometer transmission line temperature: 300℃.

10. The method for detecting the content of semi-volatile unknown substances in the extract of a Class C permanent contact medical device according to claim 1, characterized in that: In step S6, the mass spectrometry conditions of the gas chromatography-mass spectrometer are: ion source: EI; ion source temperature: 230° C.; Quadrupole temperature: 150°C; solvent delay time: 3 min; scanning mode and range: SCAN / SIM; Range: 29~550m / z.

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