Method for determining residual solvent in LXH-2103 by headspace gas chromatography

Abstract

The invention belongs to the technical field of pharmaceutical analysis, and particularly relates to a method for determining a residual solvent in LXH-2103 by headspace gas chromatography. The determination method comprises the following steps: preparing a blank solution, a reference substance solution and a sample solution, respectively injecting the blank solution, the reference substance solution and the sample solution into a headspace for balancing, injecting the solutions into a gas chromatograph in a headspace sample injection manner, recording a chromatogram, and calculating the content according to a peak area by an external standard method; the residual solvent is absolute methanol, absolute ethyl alcohol, isopropanol, dichloromethane and methylbenzene. The method for determining the residual solvents in the LXH-2103 by using the headspace gas chromatography, provided by the invention, is high in sensitivity, good in repeatability and high in accuracy, and can be used for simultaneously detecting various residual solvents in the LXH-2103, so that the quality of the LXH-2103 is ensured, and the safety of clinical medication is improved.

Description

Technical Field

[0001] The invention belongs to the technical field of drug analysis, and particularly relates to a method for determining residual solvents in LXH-2103 by utilizing headspace gas chromatography. Background Art

[0002] LXH-2103, chemical name is (±)-3-[(1 RS ,2 RS )-2-[( N , N -dimethylamino)methylene]-1-hydroxycyclohexyl]phenol hydrochloride, molecular formula: C 15 H 23 NO2•HCl, molecular weight: 285.81, its structural formula is: . In the production process of pharmaceutical raw materials and preparations, organic solvents are widely used as synthetic reaction media or extraction agents, which are dangerous. According to the toxicity and potential risks of solvents, they can be divided into four categories. The fourth part of the 2020 edition of the "Chinese Pharmacopoeia" "Determination of Residual Solvents" further clarifies the limit requirements and detection methods for residual solvents in drugs, among which gas chromatography is a commonly used analytical method. For the synthesis process of LXH-2103, it is necessary to focus on controlling the residual amounts of organic solvents such as anhydrous methanol, anhydrous ethanol, isopropanol, dichloromethane and toluene. Specifically, the residual amount of anhydrous methanol should not exceed 0.3%, the residual amount of anhydrous ethanol and isopropanol should not exceed 0.5%, and the residual limits of dichloromethane and toluene are 0.06% and 0.089%, respectively. These limit requirements are intended to ensure the safety of drugs and avoid adverse reactions in patients due to solvent residues.

[0003] Although there are headspace detection methods for detecting different solvents in the prior art, such as the headspace gas chromatography method for detecting the residual amount of organic solvents in glycine API disclosed in CN108614058A, the detection method for residual solvents in nilotinib API disclosed in CN113030323A, the detection method for residual solvents in posaconazole disclosed in CN114184721A, and the method for detecting residual solvents in poly-L-lactic acid and its preparations disclosed in CN114137095A, the above APIs are structurally different from LXH-2103. The molecular structure of LXH-2103 contains cyclohexyl, phenolic hydroxyl, N,N-dimethylaminomethylene, and it is in the form of hydrochloride. Its physical and chemical properties are similar to those of glycine and nilotinib. There are essential differences between lotinib, posaconazole, and poly-L-lactic acid. The phenol hydroxyl group (-OH) and hydrochloride (Cl⁻) lead to significantly high polarity of the raw material, which enhances the binding force between the residual solvent and the matrix. Therefore, the headspace detection leads to low solvent release efficiency. The methylene amino group (-CH=N-) and hydrochloride in the molecule are easily decomposed at high temperature, leading to the degradation of LXH-2103. The molecular weight of LXH-2103 (285.81) is significantly higher than that of glycine (75.07) and poly-L-lactic acid (repeating unit is about 144). The larger molecular weight and rigid cyclohexyl structure lead to a decrease in the diffusion rate of the solvent in the matrix. Therefore, many factors lead to unstable results such as poor repeatability and abnormal recovery rate in the residual solvent detection process of LXH-2103.

[0004] In the prior art, there have been reports on quality control methods for LXH-2103. For example, CN119165099A discloses an HPLC method for simultaneous qualitative and quantitative detection of LXH-2103 and its impurities, which achieves separation and quantification of the main components and impurities by high performance liquid chromatography, but does not yet involve a specific technical solution for controlling residual organic solvents. Summary of the invention

[0005] The technical problem to be solved by the present invention is to overcome the above-mentioned defects of the prior art and provide a method for determining residual solvents in LXH-2103 using headspace gas chromatography, which has high sensitivity, good repeatability and high accuracy and can simultaneously detect multiple residual solvents in LXH-2103, thereby ensuring the quality of LXH-2103 and improving the safety of clinical drug use.

[0006] The method for determining the residual solvent in LXH-2103 by headspace gas chromatography of the present invention comprises the following steps: preparing a blank solution, a reference solution and a test solution, respectively injecting the blank solution, the reference solution and the sample solution into the headspace for 25 to 35 minutes of equilibrium, and then injecting them into a gas chromatograph by headspace injection, recording the chromatogram, and calculating the content by peak area according to the external standard method; the residual solvent is anhydrous methanol, anhydrous ethanol, isopropanol, dichloromethane, toluene; The chromatographic conditions include: chromatographic column: a capillary column with cyanopropylphenyl-dimethylpolysiloxane as the stationary liquid; Column temperature: Initial temperature is 38-42°C, maintained for 5-6 min, then raised to 150-220°C at a rate of 10-15°C / min, maintained for 5-8 min; The headspace conditions include: headspace bottle equilibrium temperature: 80-90°C, equilibrium time: 25-35min; cycle time: 30-35min, quantitative loop temperature: 90-100°C; transmission line temperature: 100-110°C; headspace injection port temperature: 200-220°C.

[0007] The chromatographic conditions also include: Detector: FID; Detector temperature: 245-255°C; Carrier gas: nitrogen; Flow rate: 3.8-4.2 mL / min; Split ratio: 5:1; Hydrogen flow rate: 35-40 mL / min; Air flow rate: 350-400 mL / min. The chromatographic column is DB-624, 30 m×0.53 mm, with a film thickness of 3 μm.

[0008] The blank solution is an N,N-dimethylformamide solution (with water as solvent) with a volume concentration of 85% to 95%.

[0009] The concentrations of the reference substances anhydrous methanol, anhydrous ethanol, isopropanol, dichloromethane and toluene in the reference solution are 0.7398 μg / mL to 177.54 μg / mL, 1.259 μg / mL to 302.10 μg / mL, 1.276 μg / mL to 306.12 μg / mL, 0.9405 μg / mL to 37.62 μg / mL and 0.2135 μg / mL to 51.24 μg / mL, respectively, and the solvent used for dissolution and dilution is a blank solution.

[0010] The concentration of the product LXH-2103 in the test solution is 0.05~0.06g / mL, and the solvent used for dissolution and dilution is a blank solution.

[0011] The detection limits of the method for residual solvents are: 4 ppm for anhydrous methanol, 8 ppm for anhydrous ethanol, 8 ppm for isopropanol, 6 ppm for dichloromethane, and 1 ppm for toluene.

[0012] The quantitative limits of the method for residual solvents are: 15 ppm for anhydrous methanol, 25 ppm for anhydrous ethanol, 26 ppm for isopropanol, 19 ppm for dichloromethane, and 4 ppm for toluene.

[0013] The detection concentration ranges of the residual solvents in the method described are: anhydrous methanol concentration is 0.7398μg / mL to 177.54μg / mL, anhydrous ethanol concentration is 1.259μg / mL to 302.10μg / mL, isopropanol concentration is 1.276μg / mL to 306.12μg / mL, dichloromethane concentration is in the range of 0.9405μg / mL to 37.62μg / mL, and toluene concentration is 0.2135μg / mL to 51.24μg / mL.

[0014] Compared with the prior art, the present invention has the following beneficial effects: (1) The method of the present invention for determining residual solvents in LXH-2103 by headspace gas chromatography can qualitatively or quantitatively detect the contents of five residual solvents in LXH-2103, namely, anhydrous methanol, anhydrous ethanol, isopropanol, dichloromethane and toluene.

[0015] (2) The method of the present invention for determining residual solvents in LXH-2103 by headspace gas chromatography, on the one hand, provides a good reference for controlling the residual organic solvents in the production process of LXH-2103, ensuring the quality of LXH-2103, thereby improving the safety of clinical drug use; on the other hand, this method solves the cumbersome problem of using multiple methods to process and detect LXH-2103 when multiple residual solvents are present, greatly improving the convenience of operation and saving labor, time, reagents and other costs. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 is the chromatogram of the blank solution in Example 1; Figure 2 is the chromatogram of the reference substance solution in Example 1; Figure 3 is the chromatogram of the sample solution in Example 1; Figure 4 It is the chromatogram of the test sample spiked solution in Example 1. DETAILED DESCRIPTION

[0017] The present invention will be further described below in conjunction with specific embodiments.

[0018] The reagents and other materials used without indicating the manufacturer are all conventional products that can be obtained through commercial purchase.

[0019] Example 1 1. Solution preparation (1) Blank solution: Place 5.0 mL of 90% N,N-dimethylformamide in a 20 mL headspace bottle and seal.

[0020] (2) Anhydrous methanol solution: Weigh 0.3 g of anhydrous methanol into a 100 mL volumetric flask to which a small amount of 90% N,N-dimethylformamide has been added, dilute to the mark with 90% N,N-dimethylformamide, and shake to obtain anhydrous methanol stock solution; take 5.0 mL of anhydrous methanol stock solution and place it into a 100 mL volumetric flask to which a small amount of 90% N,N-dimethylformamide has been added, dilute to the mark with 90% N,N-dimethylformamide, and shake to obtain anhydrous methanol stock solution. Take 5.0 mL of this solution and place it into a 20 mL headspace bottle and seal it.

[0021] (3) Anhydrous ethanol solution: Weigh 0.5 g of anhydrous ethanol and place it in a 100 mL volumetric flask to which a small amount of 90% N,N-dimethylformamide has been added. Add 90% N,N-dimethylformamide to dilute to the mark and shake well to obtain anhydrous ethanol stock solution; take 5.0 mL of anhydrous ethanol stock solution and place it in a 100 mL volumetric flask to which a small amount of 90% N,N-dimethylformamide has been added. Add 90% N,N-dimethylformamide to dilute to the mark and shake well. Take 5.0 mL of this solution and place it in a 20 mL headspace bottle and seal it.

[0022] (4) Isopropanol solution: Weigh 0.5 g of isopropanol into a 100 mL volumetric flask to which a small amount of 90% N,N-dimethylformamide has been added, add 90% N,N-dimethylformamide to dilute to the mark, and shake well to obtain an isopropanol stock solution; take 5.0 mL of the isopropanol stock solution and place it into a 100 mL volumetric flask to which a small amount of 90% N,N-dimethylformamide has been added, add 90% N,N-dimethylformamide to dilute to the mark, and shake well. Take 5.0 mL of the solution and place it into a 20 mL headspace bottle and seal it.

[0023] (5) Dichloromethane solution: Weigh 0.06 g of dichloromethane and place it in a 100 mL volumetric flask to which a small amount of 90% N,N-dimethylformamide has been added. Add 90% N,N-dimethylformamide to dilute to the mark and shake well to obtain a dichloromethane stock solution. Take 5.0 mL of the dichloromethane stock solution and place it in a 100 mL volumetric flask to which a small amount of 90% N,N-dimethylformamide has been added. Add 90% N,N-dimethylformamide to dilute to the mark and shake well. Take 5.0 mL of the solution and place it in a 20 mL headspace bottle and seal it.

[0024] (6) Toluene solution: Weigh 0.089 g of toluene and place it in a 100 mL volumetric flask to which a small amount of 90% N,N-dimethylformamide has been added. Add 90% N,N-dimethylformamide to dilute to the mark and shake well to obtain a toluene stock solution. Take 5.0 mL of the toluene stock solution and place it in a 100 mL volumetric flask to which a small amount of 90% N,N-dimethylformamide has been added. Add 90% N,N-dimethylformamide to dilute to the mark and shake well. Take 5.0 mL of the solution and place it in a 20 mL headspace bottle and seal it.

[0025] (7) Reference solution: Weigh 0.3 g of anhydrous methanol, 0.5 g of anhydrous ethanol, 0.5 g of isopropanol, 0.06 g of dichloromethane, and 0.089 g of toluene, and place them in a 100 mL volumetric flask to which a small amount of 90% N,N-dimethylformamide has been added. Add 90% N,N-dimethylformamide to dilute to the mark, and shake well to obtain solution A; take 5.0 mL of solution A and place it in a 100 mL volumetric flask to which a small amount of 90% N,N-dimethylformamide has been added. Add 90% N,N-dimethylformamide to dilute to the mark, and shake well to obtain the reference solution. Take 5.0 mL of this solution and place it in a 20 mL headspace bottle and seal it.

[0026] (8) Sample solution: Weigh 0.25 g of sample into a 20 mL headspace bottle, add 5.0 mL of 90% N,N-dimethylformamide, and seal.

[0027] (9) Test sample spike solution: Weigh 0.25 g of sample into a 20 mL headspace vial, add 5.0 mL of reference solution, and seal.

[0028] (II) Analysis conditions: Instrument: Agilent 7890A headspace gas chromatograph; Chromatographic parameters: Chromatographic column: DB-624 (30m×0.53mm, film thickness 3μm); Column temperature: Initial temperature was 40℃ for 6min, then increased to 150℃ at a rate of 10℃ / min, and maintained for 5min; Carrier gas: nitrogen; Carrier gas flow rate: 4.0mL / min; Split ratio: 5:1; Hydrogen flow rate: 40mL / min; Air flow rate: 400mL / min; Detector: FID; Detector temperature: 250℃; Headspace conditions: headspace injection port temperature: 200°C; headspace bottle equilibrium temperature: 85°C; quantitative loop temperature: 95°C; transfer line temperature: 105°C; equilibrium time: 30 min; cycle time: 30 min.

[0029] (III) Determination: Take the solutions of (1) to (9) and inject them into the headspace for balance. Then inject them into the gas chromatograph and record the chromatogram. Calculate the content by peak area according to the external standard method. The chromatogram of the blank solution is as follows: Figure 1 The chromatogram of the reference solution is shown in Figure 2 The chromatogram of the sample solution is shown in Figure 3 The chromatogram of the spiked solution of the test sample is shown in Figure 4 The measurement results are shown in Table 1.

[0030] Table 1 Retention time of each compound

[0031] The blank solution has no significant interference at each target peak; in the spectrum of the reference solution, the separation of each target peak meets the requirements; in the spectrum of the sample solution and the mixed solution, there is no significant interfering peak near the retention time of the target peak; in the spectrum of the mixed solution, the retention time of the target peak is consistent with the retention time of the target peak in the reference solution, and the specificity meets the requirements.

[0032] Methodological verification (the chromatographic conditions and headspace conditions used are the same as those in Example 1 unless otherwise specified): a. Repeatability (1) Reference solution: Weigh 0.3 g of anhydrous methanol, 0.5 g of anhydrous ethanol, 0.5 g of isopropanol, 0.06 g of dichloromethane, and 0.089 g of toluene, and place them in a 100 mL volumetric flask to which a small amount of 90% N,N-dimethylformamide has been added. Add 90% N,N-dimethylformamide to dilute to the mark, and shake well to obtain solution A; take 5.0 mL of solution A and place it in a 100 mL volumetric flask to which a small amount of 90% N,N-dimethylformamide has been added. Add 90% N,N-dimethylformamide to dilute to the mark, and shake well to obtain reference solution. Take 6 20 mL headspace bottles, add 5.0 mL of reference solution to each bottle, and seal.

[0033] (2) Blank solution: Place 5.0 mL of 90% N,N-dimethylformamide in a 20 mL headspace bottle and seal.

[0034] (3) Repeatability test solution: Weigh 0.25 g of sample into a 20 mL headspace bottle, add 5.0 mL of reference solution, and seal. Prepare 6 more in the same way.

[0035] Take the above-mentioned reference solution, blank solution and repeatability test solution and inject them according to the chromatographic conditions, and record the chromatogram. The repeatability results are shown in Table 2.

[0036] Table 2 Repeatability results

[0037] Under the reference solution item, the RSD of the peak area of ​​anhydrous methanol was 1.4%, the RSD of the peak area of ​​anhydrous ethanol was 1.4%, the RSD of the peak area of ​​isopropanol was 1.4%, the RSD of the peak area of ​​dichloromethane was 0.77%, and the RSD of the peak area of ​​toluene was 0.81, all of which were no more than 10%; under the test solution item, the RSD of the 6 measurement results of anhydrous methanol was 0.90%, the RSD of the 6 measurement results of anhydrous ethanol was 0.98%, the RSD of the 6 measurement results of isopropanol was 1.1%, the RSD of the 6 measurement results of dichloromethane was 1.2%, and the RSD of the 6 measurement results of toluene was 1.2%, all of which were no more than 10%, all met the requirements.

[0038] b. Intermediate precision The analysts, instruments and chromatographic columns were replaced, and the precision solutions were re-prepared for testing on different dates.

[0039] (1) Reference solution: Weigh 0.3 g of anhydrous methanol, 0.5 g of anhydrous ethanol, 0.5 g of isopropanol, 0.06 g of dichloromethane, and 0.089 g of toluene, and place them in a 100 mL volumetric flask to which a small amount of 90% N,N-dimethylformamide has been added. Add 90% N,N-dimethylformamide to dilute to the mark, and shake well to obtain solution A; take 5.0 mL of solution A and place it in a 100 mL volumetric flask to which a small amount of 90% N,N-dimethylformamide has been added. Add 90% N,N-dimethylformamide to dilute to the mark, and shake well to obtain reference solution. Take 6 20 mL headspace bottles, add 5.0 mL of reference solution to each bottle, and seal.

[0040] (2) Blank solution: Place 5.0 mL of 90% N,N-dimethylformamide in a 20 mL headspace bottle and seal.

[0041] (3) Intermediate precision test solution: Weigh 0.25 g of sample into a 20 mL headspace bottle, add 5.0 mL of reference solution, and seal. Prepare 6 portions in the same way.

[0042] Take the above-mentioned reference solution, blank solution and intermediate precision test solution and inject them according to the chromatographic conditions, and record the chromatogram. The intermediate precision results are shown in Table 3.

[0043] Table 3 Intermediate precision results

[0044] Under the reference solution, the RSD of the peak area of ​​anhydrous methanol was 4.0%, the RSD of the peak area of ​​anhydrous ethanol was 4.5%, the RSD of the peak area of ​​isopropanol was 4.5%, the RSD of the peak area of ​​dichloromethane was 2.5%, and the RSD of the peak area of ​​toluene was 3.5%, all of which were less than 10%; under the test solution, the RSD of the 6 determination results of anhydrous methanol was 0.90%, and the RSD of the 12 determination results of repeatability was 2.0%; the RSD of the 6 determination results of anhydrous ethanol was 1 .1%, and the RSD of 12 measurement results with repeatability was 2.1%; the RSD of 6 measurement results of isopropanol was 1.3%, and the RSD of 12 measurement results with repeatability was 2.4%; the RSD of 6 measurement results of dichloromethane was 1.0%, and the RSD of 12 measurement results with repeatability was 2.4%; the RSD of 6 measurement results of toluene was 1.4%, and the RSD of 12 measurement results with repeatability was 2.7%; all of them were less than 10%, which met the requirements.

[0045] c. Limit of detection and limit of quantification Blank solution: Weigh anhydrous methanol, anhydrous ethanol, isopropanol, dichloromethane, and toluene, and gradually dilute with 90% N,N-dimethylformamide to obtain the quantitative limit and detection limit test solution. Take 5.0mL and place it in a 20mL headspace bottle and seal it. Take 5.0mL of 90% N,N-dimethylformamide and place it in a 20mL headspace bottle and seal it as the blank solution.

[0046] Inject the sample under the chromatographic conditions, record the chromatogram, and measure the signal-to-noise ratio S / N of each target peak. When S / N is not less than 3, the concentration of each solvent is converted to the equivalent content in the test sample as the detection limit; when S / N is not less than 10, the concentration of each solvent is converted to the equivalent content in the test sample as the quantitative limit. The results of the detection limit determination are shown in Table 4.

[0047] The calculation formula is: detection limit LOD (ppm) = minimum detection concentration (µg / mL) × 20; Limit of quantification LOQ (ppm) = minimum quantitative concentration (µg / mL) × 20.

[0048] Table 4 Results of detection limit and quantification limit determination

[0049] The detection limit of anhydrous methanol is 4ppm, the quantification limit is 15ppm, and the RSD of the peak area of ​​the six quantification limits is 2.9%; the detection limit of anhydrous ethanol is 8ppm, the quantification limit is 25ppm, and the RSD of the peak area of ​​the six quantification limits is 9.2%; the detection limit of isopropanol is 8ppm, the quantification limit is 26ppm, and the RSD of the peak area of ​​the six quantification limits is 3.0%; the detection limit of dichloromethane is 6ppm, the quantification limit is 19ppm, and the RSD of the peak area of ​​the six quantification limits is 2.6%; the detection limit of toluene is 1ppm, the quantification limit is 4ppm, and the RSD of the peak area of ​​the six quantification limits is 3.3%; the S / N of the detection limit of each target peak is not less than 3, and the S / N of the quantification limit is not less than 10, which meets the requirements.

[0050] d. Linear Examine the extent to which peak area is directly proportional to concentration within the design range.

[0051] (1) Blank solution: Place 5.0 mL of 90% N,N-dimethylformamide in a 20 mL headspace bottle and seal.

[0052] (2) Anhydrous methanol linear stock solution: Weigh 0.3 g of anhydrous methanol into a 100 mL volumetric flask to which a small amount of 90% N,N-dimethylformamide has been added. Add 90% N,N-dimethylformamide to dilute to the scale and shake well.

[0053] (3) Anhydrous ethanol linear stock solution: Weigh 0.5 g of anhydrous ethanol and place it in a 100 mL volumetric flask to which a small amount of 90% N,N-dimethylformamide has been added. Add 90% N,N-dimethylformamide to dilute to the scale and shake well.

[0054] (4) Isopropanol linear stock solution: Weigh 0.5 g of isopropanol into a 100 mL volumetric flask to which a small amount of 90% N,N-dimethylformamide has been added. Add 90% N,N-dimethylformamide to dilute to the mark and shake well.

[0055] (5) Dichloromethane linear stock solution: Weigh 0.06 g of dichloromethane and place it in a 100 mL volumetric flask to which a small amount of 90% N,N-dimethylformamide has been added. Add 90% N,N-dimethylformamide to dilute to the scale and shake well.

[0056] (6) Toluene linear stock solution: Weigh 0.089 g of toluene and place it in a 100 mL volumetric flask to which a small amount of 90% N,N-dimethylformamide has been added. Add 90% N,N-dimethylformamide to dilute to the scale and shake well.

[0057] (7) Linearity test solution ①: Take an appropriate amount of each linearity stock solution and add 90% N,N-dimethylformamide to dilute to the quantitative limit concentration.

[0058] (8) Linearity test solution ②: Take 1.0 mL of each of the linearity stock solutions (2) to (6) and place them in the same 100 mL volumetric flask. Add 90% N,N-dimethylformamide and dilute to the mark.

[0059] (9) Linearity test solution ③: Take 2.5 mL of each of the linearity stock solutions (2) to (6) and place them in the same 100 mL volumetric flask. Add 90% N,N-dimethylformamide and dilute to the mark.

[0060] (10) Linearity test solution ④: Take 5.0 mL of each of the linearity stock solutions (2) to (6) and place them in the same 100 mL volumetric flask. Add 90% N,N-dimethylformamide and dilute to the mark.

[0061] (11) Linearity test solution ⑤: Take 6.0 mL of each of the linearity stock solutions (2) to (6) and place them in the same 100 mL volumetric flask. Add 90% N,N-dimethylformamide and dilute to the mark.

[0062] Take 5.0mL of the blank solution and each linear test solution ① to ⑤ respectively and place them in a 20mL headspace bottle, seal it, inject the sample into the headspace, and record the chromatogram. Take the peak area of ​​each target peak as the ordinate and the concentration of each solvent in the linear test solution (µg / mL) as the abscissa to make a linear regression and calculate the linear equation and correlation coefficient r. The linear determination data results are shown in Table 5.

[0063] Table 5 Linearity determination data

[0064] The concentration of anhydrous methanol is in the range of 0.7398μg / mL to 177.54μg / mL, the linear equation is Y=0.9814X+0.2768, and the correlation coefficient r is 0.9998; the concentration of anhydrous ethanol is in the range of 1.259μg / mL to 302.10μg / mL, the linear equation is Y=1.1467X-1.229, and the correlation coefficient r is 0.9998; the concentration of isopropanol is in the range of 1.276μg / mL to 306.12μg / mL, The linear equation is Y=1.3569X-0.7102, and the correlation coefficient r is 0.9998; when the concentration of dichloromethane is in the range of 0.9405μg / mL to 37.62μg / mL, the linear equation is Y=1.6567X-0.1112, and the correlation coefficient r is 0.9998; when the concentration of toluene is in the range of 0.2135μg / mL to 51.24μg / mL, the linear equation is Y=5.5867X-0.0949, and the correlation coefficient r is 0.9997.

[0065] e. Accuracy (1) Blank solution: Place 5.0 mL of 90% N,N-dimethylformamide in a 20 mL headspace bottle and seal.

[0066] (2) Sample blank solution: Weigh 0.25 g of sample into a 20 mL headspace bottle, add 5.0 mL of 90% N,N-dimethylformamide, and seal.

[0067] (3) Reference solution: Weigh 0.3 g of anhydrous methanol, 0.5 g of anhydrous ethanol, 0.5 g of isopropanol, 0.06 g of dichloromethane, and 0.089 g of toluene, and place them in a 100 mL volumetric flask to which a small amount of 90% N,N-dimethylformamide has been added. Add 90% N,N-dimethylformamide to dilute to the mark, and shake well to obtain solution A; take 5.0 mL of solution A and place it in a 100 mL volumetric flask to which a small amount of 90% N,N-dimethylformamide has been added. Add 90% N,N-dimethylformamide to dilute to the mark, and shake well to obtain reference solution. Take 6 20 mL headspace bottles, add 5.0 mL of reference solution to each bottle, and seal.

[0068] (4) Accuracy test solution 1: Take an appropriate amount of each linear stock solution under the linear test item, add 90% N,N-dimethylformamide to dilute to the quantitative limit concentration solution; take three headspace bottles, pre-add 0.25g of sample, and then add 5.0mL of quantitative limit concentration solution to each bottle and seal.

[0069] (5) Accuracy test solution 2: Prepare the stock solution in the same way as the linearity test solution ③ under the linearity test. Take three headspace bottles, add 0.25 g of sample in advance, and then add 5.0 mL of the stock solution to each bottle and seal them.

[0070] (6) Accuracy test solution 3: Prepare the stock solution in the same way as the linearity test solution ④ under the linearity test item; take three headspace bottles, add 0.25 g of sample in advance, then add 5.0 mL of the stock solution to each bottle and seal.

[0071] (7) Accuracy test solution 4: Prepare the stock solution in the same way as the linearity test solution ⑤ under the linearity test item; take three headspace bottles, add 0.25 g of sample in advance, then add 5.0 mL of the stock solution to each bottle and seal.

[0072] Place the headspace bottles containing the reference solution, blank solution, sample blank solution and accuracy test solution at 85°C for 30 minutes, take 1.0mL of gas headspace injection, and record the chromatogram. The accuracy test data of anhydrous methanol, anhydrous ethanol, isopropanol, dichloromethane and toluene are shown in Table 6-10.

[0073] Calculation formula: Recovery rate (%) = , Where: A 测 is the peak area of ​​the solvent in the test solution spectrum; A 空 is the peak area of ​​the solvent in the blank solution spectrum; A 样空 is the peak area of ​​the solvent in the sample blank solution spectrum; Ā 对 is the average peak area of ​​the solvent in the spectrum of the reference solution; C 测 is the concentration of the solvent in the test solution, µg / mL; C 对 is the concentration of the solvent in the reference solution, µg / mL; W 测 is the weight of LXH-2103 added to the test solution, g; W 样空 is the weight of LXH-2103 in the sample blank solution, g.

[0074] Table 6 Anhydrous methanol accuracy test data

[0075] Table 7 Anhydrous ethanol accuracy test data

[0076] Table 8 Isopropanol accuracy test data

[0077] Table 9 Dichloromethane accuracy test data

[0078] Table 10 Toluene accuracy test data

[0079] The recovery rate of anhydrous methanol is between 97.26% and 114.46%, and the relative standard deviation of the recovery rate is 6.5%; the recovery rate of anhydrous ethanol is between 95.38% and 102.93%, and the relative standard deviation of the recovery rate is 2.4%; the recovery rate of isopropanol is between 97.81% and 107.18%, and the relative standard deviation of the recovery rate is 2.4%; the recovery rate of dichloromethane is between 102.78% and 114.42%, and the relative standard deviation of the recovery rate is 3.1%; the recovery rate of toluene is between 102.01% and 118.43%, and the relative standard deviation of the recovery rate is 5.8%; all meet the requirements.

[0080] Through the above tests on precision, linearity and accuracy, it can be determined that the analysis method is applicable when the concentration of anhydrous methanol is in the range of 0.7398μg / mL to 177.54μg / mL (equivalent to 15ppm to 3551ppm of the sample), the concentration of anhydrous ethanol is in the range of 1.259μg / mL to 302.10μg / mL (equivalent to 25ppm to 6042ppm of the sample), the concentration of isopropanol is in the range of 1.276μg / mL to 306.12μg / mL (equivalent to 26ppm to 6122ppm of the sample), the concentration of dichloromethane is in the range of 0.9405μg / mL to 37.62μg / mL (equivalent to 19ppm to 752ppm of the sample), and the concentration of toluene is in the range of 0.2135μg / mL to 51.24μg / mL (equivalent to 4ppm to 1025ppm of the sample), and the results obtained are accurate and reliable.

[0081] f. Solution stability (1) Blank solution: Place 5.0 mL of 90% N,N-dimethylformamide in a 20 mL headspace bottle and seal.

[0082] (2) Reference solution: Weigh 0.3 g of anhydrous methanol, 0.5 g of anhydrous ethanol, 0.5 g of isopropanol, 0.06 g of dichloromethane, and 0.089 g of toluene, and place them in a 100 mL volumetric flask to which a small amount of 90% N,N-dimethylformamide has been added. Add 90% N,N-dimethylformamide to dilute to the mark, and shake well to obtain solution A; take 25.0 mL of solution A and place it in a 500 mL volumetric flask to which a small amount of 90% N,N-dimethylformamide has been added. Add 90% N,N-dimethylformamide to dilute to the mark, and shake well to obtain reference solution. Take 6 20 mL headspace bottles, add 5.0 mL of reference solution to each, and seal.

[0083] (3) Test sample spiked solution: Weigh 0.25 g of sample into a 20 mL headspace vial, add 5.0 mL of reference solution, and seal.

[0084] From 0h to 120h, select appropriate time points to perform determination according to chromatographic conditions and record the chromatogram. The test results of the reference solution and the test solution are shown in Tables 11 and 12.

[0085] For the reference solution, the RSD of the peak area of ​​anhydrous methanol, anhydrous ethanol, isopropanol, dichloromethane, and toluene should not be greater than 10%, and the separation degree should not be less than 1.5; for the test sample spiked solution, the RSD of the measured value of each residual solvent peak result is not greater than 10%. It can be considered that under the residual solvent item of LXH-2103, the reference solution and the test sample spiked solution are stable.

[0086] Table 11 Test results of reference solution

[0087] Table 12 Test results of spiked solution of test sample

[0088] Within 0h-120h, under the reference solution, the peak area RSD of each chromatographic peak is no more than 10%, and the separation degree of each chromatographic peak is no more than 1.5; for the test sample spiked solution, the RSD of anhydrous methanol is 1.3%, the RSD of anhydrous ethanol is 1.3%, the RSD% of isopropanol is 1.3%, the RSD of dichloromethane is 1.1%, and the RSD of toluene is 1.2%. The RSD of each target peak is less than 10%, and the reference solution and the test sample spiked solution are stable within 120h.

[0089] Example 2 1. Solution preparation (1) Blank solution: Place 5.0 mL of 90% N,N-dimethylformamide in a 20 mL headspace bottle and seal.

[0090] (2) Reference solution: Weigh 0.3 g of anhydrous methanol, 0.5 g of anhydrous ethanol, 0.5 g of isopropanol, 0.06 g of dichloromethane, and 0.089 g of toluene, and place them in a 100 mL volumetric flask to which a small amount of 90% N,N-dimethylformamide has been added. Add 90% N,N-dimethylformamide to dilute to the mark, and shake well to obtain solution A; take 5.0 mL of solution A and place it in a 100 mL volumetric flask to which a small amount of 90% N,N-dimethylformamide has been added. Add 90% N,N-dimethylformamide to dilute to the mark, and shake well to obtain reference solution. Take 6 20 mL headspace bottles, add 5.0 mL of reference solution to each, and seal.

[0091] (3) Test sample spiked solution: Weigh 0.25 g of sample into a 20 mL headspace vial, add 5.0 mL of reference solution, and seal.

[0092] (II) Analysis conditions: Instrument: Agilent 7890A headspace gas chromatograph, FID detector; chromatographic column: DB-624 (30m×0.53mm, film thickness 3μm); chromatographic parameters: carrier gas: nitrogen; carrier gas flow rate: 4.2ml / min; split ratio: 5:1; hydrogen flow rate: 40mL / min; air flow rate: 400mL / min; detector temperature: 250℃; column temperature: the initial temperature was 40℃ and maintained for 6min, then increased to 150℃ at a rate of 10℃ / min and maintained for 5min.

[0093] Headspace detection parameters: headspace bottle equilibrium temperature: 85°C; quantitative loop temperature: 95°C; transfer line temperature: 105°C; headspace injection port temperature: 200°C; headspace equilibrium time: 30 min; cycle time: 30 min.

[0094] (III) Determination: Take the above-mentioned reference solution, blank solution and test sample spiked solution and inject them into the gas chromatograph after headspace balance, record the chromatogram, the test results of the reference solution are shown in Table 13, and the test results of the test sample spiked solution are shown in Table 14.

[0095] Table 13 Test results of reference solution

[0096] Table 14 Test results of spiked solution of test sample

[0097] In the reference solution, the RSDs of the peak areas of anhydrous methanol, anhydrous ethanol, isopropanol, dichloromethane and toluene were 1.9, 2.3, 1.5, 3.7 and 3.0, respectively, all less than 10%; in the test sample spiked solution, the separation between the chromatographic peaks was greater than 1.5, the tailing factor of each chromatographic peak was less than 1.2, the theoretical plate number of each chromatographic peak was greater than 10,000, and the measured values ​​were accurate.

[0098] Example 3 (i) The solution preparation is the same as in Example 2.

[0099] (II) Analysis conditions: Instrument: Agilent 7890A headspace gas chromatograph, FID detector; chromatographic column: DB-624 (30m×0.53mm, film thickness 3μm); chromatographic parameters: carrier gas: nitrogen; carrier gas flow rate: 3.8ml / min; split ratio: 5:1; hydrogen flow rate: 35mL / min; air flow rate: 350mL / min; detector temperature: 250℃; column temperature: the initial temperature was 40℃ and maintained for 6min, then increased to 150℃ at a rate of 10℃ / min and maintained for 5min.

[0100] Headspace detection parameters: headspace bottle equilibrium temperature: 85°C; quantitative loop temperature: 95°C; transfer line temperature: 105°C; headspace injection port temperature: 200°C; headspace equilibrium time: 30 min; cycle time: 30 min.

[0101] (III) Determination: Take the above-mentioned reference solution, blank solution and test sample spiked solution and inject them into the gas chromatograph after headspace balance, record the chromatogram, the test results of the reference solution are shown in Table 15, and the test results of the test sample spiked solution are shown in Table 16.

[0102] Table 15 Test results of reference solution

[0103] Table 16 Test results of spiked solution of test sample

[0104] In the reference solution, the RSDs of the peak areas of anhydrous methanol, anhydrous ethanol, isopropanol, dichloromethane and toluene were 2.1, 2.2, 2.0, 1.9 and 1.8, respectively, all less than 10%; in the test sample spiked solution, the separation between the chromatographic peaks was greater than 1.5, the tailing factor of each chromatographic peak was less than 1.2, the theoretical plate number of each chromatographic peak was greater than 10,000, and the measured values ​​were accurate.

[0105] Example 4 (I) Solution preparation is the same as in Example 2. (II) Analysis conditions: Instrument: Agilent 7890A headspace gas chromatograph, FID detector; chromatographic column: DB-624 (30m×0.53mm, film thickness 3μm); chromatographic parameters: carrier gas: nitrogen; carrier gas flow rate: 4.0ml / min; split ratio: 5:1; hydrogen flow rate: 40mL / min; air flow rate: 400mL / min; detector temperature: 250℃; column temperature: the initial temperature was 42℃ and maintained for 5min, then increased to 220℃ at a rate of 15℃ / min and maintained for 8min.

[0106] Headspace detection parameters: headspace bottle equilibrium temperature: 85°C; quantitative loop temperature: 95°C; transfer line temperature: 105°C; headspace injection port temperature: 200°C; headspace equilibrium time: 30 min; cycle time: 35 min.

[0107] (III) Determination: Take the above-mentioned reference solution, blank solution and test sample spiked solution and inject them into the gas chromatograph after headspace balance, record the chromatogram, the test results of the reference solution are shown in Table 17, and the test results of the test sample spiked solution are shown in Table 18.

[0108] Table 17 Test results of reference solution

[0109] Table 18 Test results of spiked solution of test sample

[0110] In the reference solution, the RSDs of the peak areas of anhydrous methanol, anhydrous ethanol, isopropanol, dichloromethane and toluene were 1.9, 1.9, 1.9, 1.4 and 1.3, respectively, all less than 10%; in the test sample spiked solution, the separation between the chromatographic peaks was greater than 1.5, the tailing factor of each chromatographic peak was less than 1.2, the theoretical plate number of each chromatographic peak was greater than 10,000, and the measured values ​​were accurate.

[0111] Example 5 (i) The solution preparation is the same as in Example 2.

[0112] (II) Analysis conditions: Instrument: Agilent 7890A headspace gas chromatograph, FID detector; chromatographic column: DB-624 (30m×0.53mm, film thickness 3μm); chromatographic parameters: carrier gas: nitrogen; carrier gas flow rate: 4.0ml / min; split ratio: 5:1; hydrogen flow rate: 40mL / min; air flow rate: 400mL / min; detector temperature: 250℃; column temperature: the initial temperature was 38℃ and maintained for 6min, then increased to 150℃ at a rate of 10℃ / min and maintained for 5min.

[0113] Headspace detection parameters: headspace bottle equilibrium temperature: 85°C; quantitative loop temperature: 95°C; transfer line temperature: 105°C; headspace injection port temperature: 200°C; headspace equilibrium time: 30 min; cycle time: 30 min.

[0114] (III) Determination: Take the above-mentioned reference solution, blank solution and test sample spiked solution and inject them into the gas chromatograph after headspace balance, record the chromatogram, the test results of the reference solution are shown in Table 19, and the test results of the test sample spiked solution are shown in Table 20.

[0115] Table 19 Test results of reference solution

[0116] Table 20 Test results of spiked solution of test sample

[0117] In the reference solution, the RSDs of the peak areas of anhydrous methanol, anhydrous ethanol, isopropanol, dichloromethane and toluene were 1.4, 1.4, 1.5, 1.0 and 0.9, respectively, all less than 10%; in the test sample spiked solution, the separation between the chromatographic peaks was greater than 1.5, the tailing factor of each chromatographic peak was less than 1.2, the theoretical plate number of each chromatographic peak was greater than 10,000, and the measured values ​​were accurate.

[0118] Example 6 (The solution preparation is the same as in Example 2.

[0119] (II) Analysis conditions: Instrument: Agilent 7890A headspace gas chromatograph, FID detector; chromatographic column: DB-624 (30m×0.53mm, film thickness 3μm); chromatographic parameters: carrier gas: nitrogen; carrier gas flow rate: 4.0ml / min; split ratio: 5:1; hydrogen flow rate: 40mL / min; air flow rate: 400mL / min; detector temperature: 250℃; column temperature: the initial temperature was 40℃ and maintained for 6min, then increased to 150℃ at a rate of 10℃ / min and maintained for 5min.

[0120] Headspace detection parameters: headspace bottle equilibrium temperature: 90°C; quantitative loop temperature: 100°C; transfer line temperature: 110°C; headspace injection port temperature: 200°C; headspace equilibrium time: 30 min; cycle time: 30 min.

[0121] (III) Determination: Take the above-mentioned reference solution, blank solution and test sample spiked solution and inject them into the gas chromatograph after headspace balance, record the chromatogram, the test results of the reference solution are shown in Table 21, and the test results of the test sample spiked solution are shown in Table 22.

[0122] Table 21 Test results of reference solution

[0123] Table 22 Test results of spiked solution of test sample

[0124] In the reference solution, the RSDs of the peak areas of anhydrous methanol, anhydrous ethanol, isopropanol, dichloromethane and toluene were 1.8, 2.1, 1.6, 1.2 and 1.2, respectively, all less than 10%; in the test sample spiked solution, the separation between the chromatographic peaks was greater than 1.5, the tailing factor of each chromatographic peak was less than 1.2, the theoretical plate number of each chromatographic peak was greater than 10,000, and the measured values ​​were accurate.

[0125] Example 7 (i) The solution preparation is the same as in Example 2.

[0126] (II) Analysis conditions: Instrument: Agilent 7890A headspace gas chromatograph, FID detector; chromatographic column: DB-624 (30m×0.53mm, film thickness 3μm); chromatographic parameters: carrier gas: nitrogen; carrier gas flow rate: 4.0ml / min; split ratio: 5:1; hydrogen flow rate: 40mL / min; air flow rate: 400mL / min; detector temperature: 250℃; column temperature: the initial temperature was 40℃ and maintained for 6min, then increased to 150℃ at a rate of 10℃ / min and maintained for 5min.

[0127] Headspace detection parameters: headspace bottle equilibrium temperature: 80°C; quantitative loop temperature: 90°C; transfer line temperature: 100°C; headspace injection port temperature: 200°C; headspace equilibrium time: 30 min; cycle time: 30 min.

[0128] (III) Determination: Take the above-mentioned reference solution, blank solution and test sample spiked solution and inject them into the gas chromatograph after headspace balance, record the chromatogram, the test results of the reference solution are shown in Table 23, and the test results of the test sample spiked solution are shown in Table 24.

[0129] Table 23 Test results of reference solution

[0130] Table 24 Test results of spiked solution of test sample

[0131] In the reference solution, the RSDs of the peak areas of anhydrous methanol, anhydrous ethanol, isopropanol, dichloromethane and toluene were 1.3, 1.4, 1.2, 1.4 and 1.5, respectively, all less than 10%; in the test sample spiked solution, the separation between the chromatographic peaks was greater than 1.5, the tailing factor of each chromatographic peak was less than 1.2, the theoretical plate number of each chromatographic peak was greater than 10,000, and the measured values ​​were accurate.

[0132] Example 8 (i) The solution preparation is the same as in Example 2.

[0133] (II) Analysis conditions: Instrument: Agilent 7890A headspace gas chromatograph, FID detector; chromatographic column: DB-624 (30m×0.53mm, film thickness 3μm); chromatographic parameters: carrier gas: nitrogen; carrier gas flow rate: 4.0ml / min; split ratio: 5:1; hydrogen flow rate: 40mL / min; air flow rate: 400mL / min; detector temperature: 255℃; column temperature: the initial temperature was 40℃ and maintained for 6min, then increased to 150℃ at a rate of 10℃ / min and maintained for 5min.

[0134] Headspace detection parameters: headspace bottle equilibrium temperature: 85°C; quantitative loop temperature: 95°C; transfer line temperature: 105°C; headspace injection port temperature: 220°C; headspace equilibrium time: 30 min; cycle time: 30 min.

[0135] (III) Determination: Take the above-mentioned reference solution, blank solution and test sample spiked solution and inject them into the gas chromatograph after headspace balance, record the chromatogram, the test results of the reference solution are shown in Table 25, and the test results of the test sample spiked solution are shown in Table 26.

[0136] Table 25 Test results of reference solution

[0137] Table 26 Test results of spiked solution of test sample

[0138] In the reference solution, the RSDs of the peak areas of anhydrous methanol, anhydrous ethanol, isopropanol, dichloromethane and toluene were 3.6, 2.8, 3.5, 5.2 and 4.4, respectively, all less than 10%; in the test sample spiked solution, the separation between the chromatographic peaks was greater than 1.5, the tailing factor of each chromatographic peak was less than 1.2, the theoretical plate number of each chromatographic peak was greater than 10,000, and the measured values ​​were accurate.

[0139] Example 9 (i) The solution preparation is the same as in Example 2.

[0140] (II) Analysis conditions: Instrument: Agilent 7890A headspace gas chromatograph, FID detector; chromatographic column: DB-624 (30m×0.53mm, film thickness 3μm); chromatographic parameters: carrier gas: nitrogen; carrier gas flow rate: 4.0ml / min; split ratio: 5:1; hydrogen flow rate: 40mL / min; air flow rate: 400mL / min; detector temperature: 245℃; column temperature: the initial temperature was 40℃ and maintained for 6min, then increased to 150℃ at a rate of 10℃ / min and maintained for 5min.

[0141] Headspace detection parameters: headspace bottle equilibrium temperature: 85°C; quantitative loop temperature: 95°C; transfer line temperature: 105°C; headspace injection port temperature: 200°C; headspace equilibrium time: 30 min; cycle time: 30 min.

[0142] (III) Determination: Take the above-mentioned reference solution, blank solution and test sample spiked solution and inject them into the gas chromatograph after headspace balance, record the chromatogram, the test results of the reference solution are shown in Table 27, and the test results of the test sample spiked solution are shown in Table 28.

[0143] Table 27 Test results of reference solution

[0144] Table 28 Test results of spiked solution of test sample

[0145] In the reference solution, the RSDs of the peak areas of anhydrous methanol, anhydrous ethanol, isopropanol, dichloromethane and toluene were 1.1, 1.3, 1.2, 1.1 and 1.0, respectively, all less than 10%; in the test sample spiked solution, the separation between the chromatographic peaks was greater than 1.5, the tailing factor of each chromatographic peak was less than 1.2, the theoretical plate number of each chromatographic peak was greater than 10,000, and the measured values ​​were accurate.

[0146] Example 10 (i) The solution preparation is the same as in Example 2.

[0147] (II) Analysis conditions: Instrument: Agilent 7890A headspace gas chromatograph, FID detector; chromatographic column: DB-624 (30m×0.53mm, film thickness 3μm); chromatographic parameters: carrier gas: nitrogen; carrier gas flow rate: 4.0ml / min; split ratio: 5:1; hydrogen flow rate: 40mL / min; air flow rate: 400mL / min; detector temperature: 250℃; column temperature: the initial temperature was 40℃ and maintained for 6min, then increased to 150℃ at a rate of 10℃ / min and maintained for 5min.

[0148] Headspace detection parameters: headspace bottle equilibrium temperature: 85°C; quantitative loop temperature: 95°C; transfer line temperature: 105°C; headspace injection port temperature: 200°C; headspace equilibrium time: 35 min; cycle time: 30 min.

[0149] (III) Determination: Take the above-mentioned reference solution, blank solution and test sample spiked solution and inject them into the gas chromatograph after headspace balance, record the chromatogram, the test results of the reference solution are shown in Table 29, and the test results of the test sample spiked solution are shown in Table 30.

[0150] Table 29 Test results of reference solution

[0151] Table 30 Test results of spiked solution of test sample

[0152] In the reference solution, the RSDs of the peak areas of anhydrous methanol, anhydrous ethanol, isopropanol, dichloromethane and toluene were 1.4, 1.2, 1.3, 1.1 and 1.1, respectively, all less than 10%; in the test sample spiked solution, the separation between the chromatographic peaks was greater than 1.5, the tailing factor of each chromatographic peak was less than 1.2, the theoretical plate number of each chromatographic peak was greater than 10,000, and the measured values ​​were accurate.

[0153] Embodiment 11 (i) The solution preparation is the same as in Example 2.

[0154] (II) Analysis conditions: Instrument: Agilent 7890A headspace gas chromatograph, FID detector; chromatographic column: DB-624 (30m×0.53mm, film thickness 3μm); chromatographic parameters: carrier gas: nitrogen; carrier gas flow rate: 4.0ml / min; split ratio: 5:1; hydrogen flow rate: 40mL / min; air flow rate: 400mL / min; detector temperature: 250℃; column temperature: the initial temperature was 40℃ and maintained for 6min, then increased to 150℃ at a rate of 10℃ / min and maintained for 5min.

[0155] Headspace detection parameters: headspace bottle equilibrium temperature: 85°C; quantitative loop temperature: 95°C; transfer line temperature: 105°C; headspace injection port temperature: 200°C; headspace equilibrium time: 25 min; cycle time: 30 min.

[0156] (III) Determination: Take the above-mentioned reference solution, blank solution and test sample spiked solution and inject them into the gas chromatograph after headspace balance, record the chromatogram, the test results of the reference solution are shown in Table 31, and the test results of the test sample spiked solution are shown in Table 32.

[0157] Table 31 Test results of reference solution

[0158] Table 32 Test results of spiked solution of test sample

[0159] In the reference solution, the RSDs of the peak areas of anhydrous methanol, anhydrous ethanol, isopropanol, dichloromethane and toluene were 1.6, 1.8, 1.4, 0.5 and 0.5, respectively, all less than 10%; in the test sample spiked solution, the separation between the chromatographic peaks was greater than 1.5, the tailing factor of each chromatographic peak was less than 1.2, the theoretical plate number of each chromatographic peak was greater than 10,000, and the measured values ​​were accurate.

[0160] Comparative Example 1 Instrument: Agilent 7890A headspace gas chromatograph, FID detector; chromatographic column: DB-624 (30m×0.53mm, film thickness 3μm); chromatographic parameters: carrier gas: nitrogen; carrier gas flow rate: 4.0mL / min; split ratio: 5:1; hydrogen flow rate: 40mL / min; air flow rate: 400mL / min; detector temperature: 250℃; headspace injection port temperature: 200℃; column temperature: the initial temperature is 40℃ and maintained for 5min, then increased to 120℃ at a rate of 10℃ / min and maintained for 5min.

[0161] Headspace detection parameters: headspace bottle equilibrium temperature: 80°C; quantitative loop temperature: 90°C; transfer line temperature: 100°C; headspace equilibrium time: 30 min; cycle time: 30 min.

[0162] (1) Blank solution: Place 5.0 mL of N,N-dimethylformamide in a 20 mL headspace bottle and seal.

[0163] (2) Reference solution: Weigh 0.3 g of anhydrous methanol, 0.5 g of anhydrous ethanol, 0.5 g of isopropanol, 0.06 g of dichloromethane, and 0.089 g of toluene, and place them in a 50 mL volumetric flask to which a small amount of N,N-dimethylformamide has been added. Add N,N-dimethylformamide to dilute to the mark, and shake well to obtain solution A; take 5.0 mL of solution A and place it in a 100 mL volumetric flask to which a small amount of N,N-dimethylformamide has been added. Add N,N-dimethylformamide to dilute to the mark, and shake well to obtain reference solution. Take 5.0 mL of the reference solution and place it in a 20 mL headspace bottle and seal it.

[0164] (3) Test sample spiked solution: Weigh 0.50 g of sample into a 20 mL headspace vial, add 5.0 mL of reference solution, and seal.

[0165] Take the above-mentioned reference solution, blank solution and test solution spiked with the sample according to the chromatographic conditions and inject them, and record the chromatogram. The test results of the reference solution are shown in Table 33, and the test results of the test solution spiked with the sample are shown in Table 34.

[0166] Table 33 Test results of reference solution

[0167] Table 34 Test results of spiked solution of test sample

[0168] During the experiment, it was found that the test sample was not easily soluble in N,N-dimethylformamide. The experimental results showed that the chromatographic peak area of ​​each solvent peak in the test sample spiked solution was larger than the chromatographic peak area of ​​each solvent peak in the reference solution, indicating that if N,N-dimethylformamide is used as the blank solvent, the recovery rate of each residual solvent to be tested will be too high, and N,N-dimethylformamide is not suitable for the blank solvent of this test method.

[0169] Comparative Example 2 Instrument: Agilent 7890A headspace gas chromatograph, FID detector; chromatographic column: DB-624 (30m×0.53mm, film thickness 3μm); chromatographic parameters: carrier gas: nitrogen; carrier gas flow rate: 4.0mL / min; split ratio: 5:1; hydrogen flow rate: 40mL / min; air flow rate: 400mL / min; detector temperature: 250℃; headspace injection port temperature: 200℃; column temperature: the initial temperature is 40℃ and maintained for 6min, then increased to 150℃ at a rate of 10℃ / min and maintained for 5min.

[0170] Headspace detection parameters: headspace bottle equilibrium temperature: 85°C; quantitative loop temperature: 95°C; transfer line temperature: 105°C; headspace equilibrium time: 30 min; cycle time: 30 min.

[0171] (1) Blank solution: Place 5.0 mL of 50% N,N-dimethylformamide in a 20 mL headspace bottle and seal.

[0172] (2) Reference solution: Weigh 0.3 g of anhydrous methanol, 0.5 g of anhydrous ethanol, 0.5 g of isopropanol, 0.06 g of dichloromethane, and 0.089 g of toluene, and place them in a 100 mL volumetric flask to which a small amount of 50% N,N-dimethylformamide has been added. Add 50% N,N-dimethylformamide to dilute to the mark, and shake well to obtain solution A; take 5.0 mL of solution A and place it in a 100 mL volumetric flask to which a small amount of 50% N,N-dimethylformamide has been added. Add 50% N,N-dimethylformamide to dilute to the mark, and shake well to obtain reference solution. Take 5.0 mL of the reference solution and place it in a 20 mL headspace bottle and seal it.

[0173] (3) Test sample spiked solution: Weigh 0.25 g of sample into a 20 mL headspace vial, add 5.0 mL of reference solution, and seal.

[0174] Take the above-mentioned reference solution, blank solution and test sample spiked solution and inject according to the chromatographic conditions, and record the chromatogram. The test results of the reference solution are shown in Table 35, and the test results of the test sample spiked solution are shown in Table 36.

[0175] Table 35 Test results of reference solution

[0176] Table 36 Test results of spiked solution of test sample

[0177] During the experiment, it was found that continuous injections left residual toluene in the instrument, resulting in residual interference of chromatographic peaks at the retention time of the toluene chromatogram in the subsequent blank solution chromatogram after the injection of the solution containing toluene, indicating that 50% N,N-dimethylformamide is not suitable as a blank solvent for this test method.

[0178] Comparative Example 3 Instrument: Agilent 7890A headspace gas chromatograph, FID detector; chromatographic column: DB-624 (30m×0.53mm, film thickness 3μm); chromatographic parameters: carrier gas: nitrogen; carrier gas flow rate: 4.0mL / min; split ratio: 5:1; hydrogen flow rate: 40mL / min; air flow rate: 400mL / min; detector temperature: 250℃; headspace injection port temperature: 200℃; column temperature: the initial temperature is 40℃ and maintained for 6min, then increased to 200℃ at a rate of 20℃ / min and maintained for 5min.

[0179] Headspace detection parameters: headspace bottle equilibrium temperature: 80°C; quantitative loop temperature: 90°C; transfer line temperature: 100°C; headspace equilibrium time: 30 min; cycle time: 30 min.

[0180] (1) Blank solution: Place 5.0 mL of dimethyl sulfoxide in a 20 mL headspace bottle and seal.

[0181] (2) Reference solution: Weigh 0.3 g of anhydrous methanol, 0.5 g of anhydrous ethanol, 0.5 g of isopropanol, 0.06 g of dichloromethane, and 0.089 g of toluene, and place them in a 50 mL volumetric flask to which a small amount of dimethyl sulfoxide has been added. Add dimethyl sulfoxide to dilute to the mark, and shake well to obtain solution A. Take 5.0 mL of solution A and place it in a 100 mL volumetric flask to which a small amount of dimethyl sulfoxide has been added. Add dimethyl sulfoxide to dilute to the mark, and shake well to obtain reference solution. Take 5.0 mL of the reference solution and place it in a 20 mL headspace bottle and seal it.

[0182] (3) Test sample spiked solution: Weigh 0.50 g of sample into a 20 mL headspace vial, add 5.0 mL of reference solution, and seal.

[0183] Take the above-mentioned reference solution, blank solution and test sample spiked solution and inject according to the chromatographic conditions, and record the chromatogram. The test results of the reference solution are shown in Table 37, and the test results of the test sample spiked solution are shown in Table 38.

[0184] Table 37 Test results of reference solution

[0185] Table 38 Test results of spiked solution of test sample

[0186] During the experiment, it was found that the test sample was not easily soluble in dimethyl sulfoxide. The experimental results showed that the chromatographic peak area of ​​each solvent peak in the test sample spiked solution was larger than the chromatographic peak area of ​​each solvent peak in the reference solution, indicating that if dimethyl sulfoxide is used as the blank solvent, the recovery rate of each residual solvent to be tested will be too high, and dimethyl sulfoxide is not suitable for the blank solvent of this test method.

Claims

1. A method for determining residual solvents in LXH-2103 using headspace gas chromatography, characterized in that: Prepare a blank solution, a reference solution and a test solution, inject the blank solution, the reference solution and the sample solution into the headspace balance respectively, and then inject them into the gas chromatograph by headspace injection, record the chromatogram, and calculate the content by peak area according to the external standard method; the residual solvent is anhydrous methanol, anhydrous ethanol, isopropanol, dichloromethane, toluene; The blank solution is an N,N-dimethylformamide solution with a volume concentration of 85% to 95%.

2. The method for determining residual solvents in LXH-2103 by headspace gas chromatography according to claim 1, characterized in that: The chromatographic conditions include: chromatographic column: a capillary column with cyanopropylphenyl-dimethylpolysiloxane as a stationary liquid; column temperature: the initial temperature is 38-42°C, maintained for 5-6 minutes, and then increased to 150-220°C at a speed of 10-15°C / min, and maintained for 5-8 minutes; The headspace conditions include: headspace bottle equilibrium temperature: 80-90°C, equilibrium time: 25-35min; and cycle time of 30-35min.

3. The method for determining residual solvents in LXH-2103 by headspace gas chromatography according to claim 2, characterized in that: The chromatographic conditions also include: detector: FID; detector temperature: 245-255° C.; carrier gas: nitrogen; flow rate: 3.8-4.2 mL / min; split ratio: 5:1; hydrogen flow: 35-40 mL / min; and air flow: 350-400 mL / min.

4. The method for determining residual solvents in LXH-2103 by headspace gas chromatography according to claim 3, characterized in that: The headspace conditions also include: the temperature of the quantitative loop is 90-100°C; the temperature of the transmission line is 100-110°C; and the temperature of the headspace injection port is 200-220°C.

5. The method for determining residual solvents in LXH-2103 by headspace gas chromatography according to claim 4, characterized in that: The chromatographic column is DB-624, 30m×0.53mm, and has a film thickness of 3μm.

6. The method for determining residual solvents in LXH-2103 by headspace gas chromatography according to claim 1, characterized in that: The solvent used for dissolving and diluting the reference solution is the blank solution.

7. The method for determining residual solvents in LXH-2103 by headspace gas chromatography according to claim 6, characterized in that: The concentration of the product LXH-2103 in the test solution is 0.05~0.06g / mL, and the solvent used for dissolution and dilution is a blank solution.

8. The method for determining residual solvents in LXH-2103 by headspace gas chromatography according to claim 1, characterized in that: The detection limits of the method for residual solvents are: 4 ppm for anhydrous methanol, 8 ppm for anhydrous ethanol, 8 ppm for isopropanol, 6 ppm for dichloromethane, and 1 ppm for toluene.

9. The method for determining residual solvents in LXH-2103 by headspace gas chromatography according to claim 1, characterized in that: The quantitative limits of the method for residual solvents are: 15 ppm for anhydrous methanol, 25 ppm for anhydrous ethanol, 26 ppm for isopropanol, 19 ppm for dichloromethane, and 4 ppm for toluene.

10. The method for determining residual solvents in LXH-2103 by headspace gas chromatography according to claim 1, characterized in that: The detection concentration ranges of the residual solvents in the method described are: anhydrous methanol concentration is 0.7398μg / mL to 177.54μg / mL, anhydrous ethanol concentration is 1.259μg / mL to 302.10μg / mL, isopropanol concentration is 1.276μg / mL to 306.12μg / mL, dichloromethane concentration is in the range of 0.9405μg / mL to 37.62μg / mL, and toluene concentration is 0.2135μg / mL to 51.24μg / mL.

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