Analysis method for detecting multiple residual solvents in drug

Abstract

An analysis method for detecting multiple residual solvents during the preparation process of a drug. In the method, a gas chromatographic method is utilized to simultaneously detect 21 organic solvents, i.e. methanol, tetrahydrofuran, ethanol, cyclohexane, diethyl ether, isopropyl acetate, acetone, n-heptane, isopropanol, n-butyl alcohol, acetonitrile, dioxane, dichloromethane, pyridine, tert-butyl alcohol, toluene, tert-butyl methyl ether, N,N-dimethylformamide, n-hexane, dimethyl sulfoxide and ethyl acetate. The method is free from influence of drug types, can be applied to the content detection of multiple residual solvents in drugs, has simple operation and a wide usable range, and saves on the time and cost for drug detection.

Description

An analytical method for detecting multiple residual solvents in drugs Technical Field

[0001] The invention belongs to the field of analytical chemistry, and particularly relates to a method for detecting multiple residual solvents in medicines by using gas chromatography. Background Art

[0002] Residual solvents in pharmaceuticals refer to volatile organic compounds used in the production of APIs, excipients, and formulations but not completely removed during the manufacturing process. In API synthesis, selecting the appropriate solvent can increase yield or determine drug properties such as crystal form, purity, and dissolution rate. In biopharmaceuticals, selecting the right solvent increases the solubility of materials during production, such as in ADCs, where an appropriate solvent is used to dissolve intermediate toxin linkers. Therefore, organic solvents are essential and critical substances in drug synthesis reactions. When residual solvent levels in a drug exceed safety limits, they can pose a risk to humans or the environment. Therefore, it is crucial to research and effectively control the organic solvents and reaction materials used in the drug manufacturing process during drug registration applications. The control of residual solvents has received increasing attention.

[0003] The International Conference on Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) harmonized guidelines require that residual solvents in finished pharmaceutical products must be controlled within specified limits. Currently, the methods for determining residual solvents in pharmaceuticals include loss on drying, spectrophotometry, and gas chromatography. Loss on drying measures the residual solvent content by measuring the loss of mass of the sample during heating. Spectrophotometry can use the reaction between a specific solvent and a specific chemical reagent to determine the residual solvent in a pharmaceutical. In the prior art, headspace gas chromatography is mainly used to determine the residual amount of organic solvents in pharmaceuticals. Since gas chromatography is a specific method for detecting residual organic solvents, the detection method can only detect solvent residues in a targeted manner and cannot simultaneously detect organic solvents used in the pharmaceutical synthesis process. Due to the wide variety of organic solvents, it is necessary to provide an analytical method during the pharmaceutical research and development process that is not affected by the type of drug, can be applied to a variety of drugs, and can simultaneously detect the content of multiple organic solvents.

[0004] Summary of the Invention

[0005] The purpose of the present invention is to provide an analytical method for simultaneously detecting multiple residual solvents in drugs, thereby achieving effective control of drug quality and ensuring the safety and controllability of subsequent drug quality.

[0006] To achieve the above object, the present invention adopts the following technical solutions:

[0007] A gas chromatography analysis method for simultaneously detecting multiple residual solvents in a drug, wherein the gas chromatography conditions of the analysis method include:

[0008] Inlet temperature: 200-250℃;

[0009] Column box heating program: initial column temperature is 30-40°C, holding time is 6-10min, preferably holding time is 8-10min, more preferably holding time is 6min, 8min or 10min, heating to 220°C at a rate of 15-25°C per minute, holding time after heating is 3-7min, preferably holding time is 5-7min, more preferably holding time is 3min, 5min or 7min.

[0010] In certain embodiments of the present invention, the injection port temperature is preferably 200°C, 230°C or 250°C.

[0011] In certain embodiments of the present invention, the initial temperature in the column oven temperature program is preferably 30°C, 35°C or 40°C.

[0012] In certain embodiments of the present invention, the rate of heating to 220° C. in the temperature heating program is preferably 15° C. / min, 20° C. / min, or 25° C. / min.

[0013] In certain embodiments of the present invention, the analytical method reference substance or test substance needs to be diluted with a diluent before injection.

[0014] In certain embodiments of the present invention, the diluent is N-methylpyrrolidone.

[0015] In certain embodiments of the present invention, the detector used in the analysis method is a hydrogen flame ionization detector.

[0016] In certain embodiments of the present invention, the chromatographic column selected for the analytical method is a medium-polarity gas chromatography capillary column or a non-polar gas chromatography capillary column.

[0017] In certain embodiments of the present invention, the medium-polarity gas chromatography capillary column is a capillary chromatography column using 6% cyanopropylphenyl-94% dimethylpolysiloxane as a stationary phase. Preferably, the medium-polarity gas chromatography capillary column is a VF624 capillary chromatography column.

[0018] In certain embodiments of the present invention, the non-polar gas chromatography capillary column is a capillary chromatography column using 100% dimethylpolysiloxane as a stationary phase. Preferably, the non-polar gas chromatography capillary column is an HP-1 capillary chromatography column.

[0019] In certain embodiments of the present invention, the detection temperature of the detector is greater than 200°C.

[0020] In certain embodiments of the present invention, the detection temperature of the detector is preferably 200-300°C, more preferably 250-300°C.

[0021] In certain embodiments of the present invention, the detection temperature of the detector is preferably 200°C, 250°C or 300°C.

[0022] In certain embodiments of the present invention, the carrier gas of the analytical method is an inert gas. Preferably, the carrier gas is nitrogen.

[0023] In certain embodiments of the present invention, the carrier gas flow rate in the gas chromatograph is 2.0-3.0 ml / min.

[0024] In certain embodiments of the present invention, the carrier gas flow rate in the gas chromatograph is preferably 2.0 ml / min or 3.0 ml / min.

[0025] In certain embodiments of the present invention, the analysis method uses split injection with a split ratio of 1-10:1, preferably a split ratio of 5-10:1, and more preferably a split ratio of 1:1, 5:1 or 10:1.

[0026] In certain embodiments of the present invention, the headspace equilibrium temperature of the analytical method is greater than 70°C, preferably 70-90°C, and more preferably 70°C or 90°C.

[0027] In certain embodiments of the present invention, the plurality of residual solvents comprises two or more of methanol, tetrahydrofuran, ethanol, cyclohexane, diethyl ether, isopropyl acetate, acetone, n-heptane, isopropyl alcohol, n-butanol, acetonitrile, dioxane, dichloromethane, pyridine, tert-butanol, toluene, tert-butyl methyl ether, N,N-dimethylformamide (DMF), n-hexane, dimethyl sulfoxide (DMSO), and ethyl acetate.

[0028] Preferably, the plurality of residual solvents comprises three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more, eleven or more, twelve or more, thirteen or more, fourteen or more, fifteen or more, sixteen or more, seventeen or more, eighteen or more, nineteen or more, or twenty or more of the group consisting of methanol, tetrahydrofuran, ethanol, cyclohexane, diethyl ether, isopropyl acetate, acetone, n-heptane, isopropyl alcohol, n-butanol, acetonitrile, dioxane, dichloromethane, pyridine, tert-butyl alcohol, toluene, tert-butyl methyl ether, N,N-dimethylformamide, n-hexane, dimethyl sulfoxide, and ethyl acetate.

[0029] In certain embodiments of the present invention, the plurality of residual solvents are one or more combinations of methanol, tetrahydrofuran, ethanol, cyclohexane, diethyl ether, isopropyl acetate, acetone, n-heptane, isopropyl alcohol, n-butanol, acetonitrile, dioxane, dichloromethane, pyridine, tert-butanol, toluene, tert-butyl methyl ether, N,N-dimethylformamide, n-hexane, dimethyl sulfoxide and ethyl acetate.

[0030] In certain embodiments of the present invention, the analytical method can be used to detect residual solvents in a drug, wherein the drug is a biological targeted drug or a chemical targeted drug. Preferably, the biological targeted drug is one or more of a monoclonal antibody, a biclonal antibody, and an antibody-drug conjugate (ADC).

[0031] The antibody-drug conjugate (ADC) described in the present invention comprises an Ab or an antigen-binding Ab fragment and a drug conjugated to the Ab or antigen-binding Ab fragment, wherein the drug is an anticancer drug, an antiproliferative drug, a cytotoxic drug, an antiangiogenic drug, an antithrombotic drug, an apoptotic drug, an immunostimulatory drug, an antimicrobial drug, an antibiotic drug, an antiviral drug, an anti-inflammatory drug, an antifibrotic drug, an immunosuppressive drug, a steroid, a bronchodilator, a beta-blocker, a matrix metalloproteinase inhibitor, an ADAM12 inhibitor, an ADAM12 signaling inhibitor, an enzyme, a hormone, a neurotransmitter, a toxin, a radioisotope, a compound, a small molecule, a small molecule inhibitor, a protein, a peptide, a vector, a plasmid, a viral particle, a nanoparticle, a DNA molecule, an RNA molecule, siRNA, shRNA, microRNA, an oligonucleotide or an imaging drug.

[0032] All technical features disclosed in this specification, or all steps in the methods or processes disclosed, except for mutually exclusive technical features and / or steps, can be combined in any manner.

[0033] The beneficial effects of the present invention are:

[0034] 1. The existing technology requires the development of multiple analytical methods to detect multiple residual solvents in drugs, or different analytical methods must be developed for different drugs to achieve the purpose of detecting residual solvents in different drugs. The present invention uses a single gas chromatography analysis method to achieve the purpose of effectively separating and analyzing up to 21 solvents simultaneously. The analytical method of the present invention has good precision, good resolution, high sensitivity, and good linear correlation.

[0035] 2. The analytical method of the present invention is not affected by the type of drug. As long as the solvent used in the drug synthesis process is included in the range of 21 solvents defined in the present invention, whether it is one or more, the analytical method of the present invention can be used to confirm at one time whether the drug has relevant solvent residues.

[0036] 3. The analytical method of the present invention is simple to operate, has a short drug detection time, and has a low detection cost. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] FIG1 is a gas chromatogram of the chromatographic column HP-1 investigated in Example 3;

[0038] FIG2 is a gas chromatogram of the blank solvent of Example 7;

[0039] FIG3 is a gas chromatogram of reference solution 1 of Example 7;

[0040] FIG4 is a gas chromatogram of the test solution of compound of formula I batch 01 in Example 7. DETAILED DESCRIPTION

[0041] The following is a further detailed description of the gas phase detection and analysis method involved in the present invention through examples, but this should not be understood as the scope of the above-mentioned subject matter of the present invention being limited to the following examples. All technologies implemented based on the above-mentioned contents of the present invention fall within the scope of the present invention.

[0042] Example 1

[0043] 1. Test instruments and reagents

[0044] Table 1 Instruments

[0045] 2. Chromatographic conditions

[0046] Chromatographic column: capillary column with 6% cyanopropylphenyl-94% dimethylpolysiloxane as stationary phase

[0047] Sample dilution solvent: N-methylpyrrolidone

[0048] Inlet temperature: 230°C

[0049] Detector: Hydrogen flame ionization detector

[0050] Carrier gas: nitrogen

[0051] Carrier gas flow rate: 2.0ml / min

[0052] Heating program: Initial column temperature is 35°C, maintained for 8 minutes, then heated to 220°C at a rate of 20°C per minute, maintained for 5 minutes

[0053] Detector temperature: 300°C

[0054] Split ratio: 10:1

[0055] Headspace bottle equilibrium temperature: 90℃, equilibrium for 20 minutes

[0056] Quantitative loop temperature: 100°C

[0057] Transmission line temperature: 110°C

[0058] 3. Solution Preparation

[0059] 3.1 Preparation of reference substance stock solution

[0060] Take a 100ml volumetric flask, weigh into 20ml N-methylpyrrolidone, and weigh in 0.3041g methanol, 0.5001g ethanol, 0.5180g ether, 0.5071g acetone, 0.4996g isopropanol, 0.0417g acetonitrile, 0.065g dichloromethane, 0.5076g tert-butanol, 0.0297g n-hexane, 0.5080g ethyl acetate, 0.0760g tetrahydrofuran, 0.3824g cyclohexane, 0.5028g isopropyl acetate, 0.5004g n-heptane, 0.5103g n-butanol, 0.0422g dioxane, 0.0209g pyridine, 0.0914g toluene, 0.0908g DMF, 0.5455g Dissolve DMSO and 0.5033 g of tert-butyl methyl ether, add N-methylpyrrolidone to the mark, and shake well to serve as the reference stock solution.

[0061] 3.2 Preparation of reference solution

[0062] Accurately measure 1 ml of the reference stock solution, place it in a 10 ml volumetric flask, add N-methylpyrrolidone to dilute to the scale, and shake well; accurately transfer 1 ml, place it in an empty bottle, and cap it as the reference solution.

[0063] 4. System suitability test

[0064] The reference solution was used as the system suitability test solution. Headspace injection was performed on this solution and the chromatographic conditions described above were followed. The chromatogram was recorded. Under these conditions, the components were well separated, with no interference from the blank solvent. Retention times for the components are shown in Table 2.

[0065] Table 2 Retention time of each component

[0066] 5. Verification Process

[0067] 5.1 Exclusivity

[0068] The chromatographic separation obtained from the system suitability test is shown in Table 3 below:

[0069] Table 3 Separation of components

[0070] 5.2 Limit of Quantitation and Limit of Detection

[0071] 5.2.1 Experimental process

[0072] Take appropriate amounts of methanol, tetrahydrofuran, ethanol, cyclohexane, ether, isopropyl acetate, acetone, n-heptane, isopropanol, n-butanol, acetonitrile, dioxane, dichloromethane, pyridine, tert-butanol, toluene, tert-butyl methyl ether, N,N-dimethylformamide, n-hexane, dimethyl sulfoxide and ethyl acetate, accurately weigh them, dissolve them in N-methylpyrrolidone to make solutions of appropriate concentrations, and determine them under the above-mentioned chromatographic conditions. The quantification limit is calculated based on an S / N of not less than 10 and a concentration of not more than 30% of the respective limit concentrations. The detection limit is calculated based on an S / N of not less than 3 and a concentration of not more than 10% of the respective limit concentrations.

[0073] 5.2.2 Results

[0074] The results of the limit of quantification and detection are shown in Table 4.

[0075] Table 4 Summary of the quantification limit and detection limit of each component

[0076] 5.3 Linearity

[0077] 5.3.1 Preparation of linear solution

[0078] Pipette 2.5 ml of "3.1 Reference Stock Solution" into a 25 ml volumetric flask, add N-methylpyrrolidone to the mark, shake well, and pipette 1000 μl into five 20 ml headspace bottles, roll on the caps and seal them as reference solution.

[0079] The reference solution was diluted step by step to different concentrations; each solution was injected and analyzed from low to high concentration according to the above chromatographic conditions.

[0080] 5.3.2 Linearity results

[0081] The linearity and range of each component were statistically analyzed, and the measurement results are shown in Table 5.

[0082] Table 5 Summary of linearity and range of each component

[0083] The linear relationship between the residual solvent concentration and the peak area was good from the limit of quantification to 200% of the limit concentration.

[0084] The above verification process and results prove that the chromatographic conditions can accurately and effectively detect 21 solvents. The method is simple, highly sensitive, precise and accurate.

[0085] Example 2

[0086] This example investigates the effect of the temperature program maintenance time on the gas chromatography analysis results. The different temperature programs set in the experiment are shown in Table 6. The other experimental conditions are the same as in Example 1. The injected sample is the 3.2 reference solution in Example 1. The experimental results are shown in Table 6 below.

[0087] Table 6 Results of optimization of heating program holding time

[0088] From the experimental results of the temperature program holding time in Table 6, it can be seen that when the initial temperature holding time is 5 minutes, it is impossible to achieve complete separation of all 21 solvents. However, when the initial temperature holding time is set to 6-10 minutes and the temperature is raised to 220°C and held for 3-7 minutes, chromatographic detection results that meet the analysis requirements can be obtained.

[0089] Example 3

[0090] This example investigates the effect of the chromatographic column on the gas chromatography analysis results. The experiment uses a chromatographic column different from that used in Example 1, as shown in Table 7. The remaining experimental conditions are the same as those in Example 1. The injected sample is the 3.2 reference solution in Example 1. The experimental results are shown in Table 7 and Figure 1 below.

[0091] Table 7 Results of column selection

[0092] From the experimental results of the chromatographic column investigation in Table 7, it can be seen that the HP-1 chromatographic column can obtain chromatographic detection results that meet the analysis requirements.

[0093] Example 4

[0094] This example investigates the effects of initial temperature and heating rate on gas chromatography analysis results. The different initial temperatures and heating rates set in the experiment are shown in Table 8. The remaining experimental conditions are the same as in Example 1. The injected sample is the 3.2 reference solution in Example 1. The experimental results are shown in Table 8 below.

[0095] Table 8 Results of initial temperature and heating rate optimization

[0096] From the experimental results of initial temperature and heating rate optimization in Table 8, it can be seen that when the initial temperature is 30-40°C and the heating rate is 15-25°C / min, chromatographic detection results that meet the analysis requirements can be obtained.

[0097] Example 5

[0098] This example investigates the effects of the injection port temperature, detector temperature, and headspace vial equilibrium temperature on the gas chromatography analysis results. The different injection port temperatures, detector temperatures, and headspace vial equilibrium temperatures set in the experiment are shown in Table 9. The remaining experimental conditions are the same as in Example 1. The injected sample is the 3.2 reference solution in Example 1. The experimental results are shown in Table 9 below.

[0099] Table 9 Optimization results of injection port temperature, detector temperature, and headspace bottle equilibrium temperature

[0100] From the experimental results of the injection port temperature, detector temperature and headspace bottle equilibrium temperature in Table 9, it can be seen that when the injection port temperature is 200-250℃, the detector temperature is 200-300℃ and the headspace bottle equilibrium temperature is 70-90℃, chromatographic detection results that meet the analysis requirements can be obtained.

[0101] Example 6

[0102] This example investigates the effects of split ratio and carrier gas flow rate on gas chromatography analysis results. The different split ratios and carrier gas flow rates set in the experiment are shown in Table 10. The remaining experimental conditions are the same as in Example 1. The injected sample is the 3.2 reference solution in Example 1. The experimental results are shown in Table 10 below.

[0103] Table 10 Results of optimization of split ratio and carrier gas flow rate

[0104] Table 10 shows that the split ratio and carrier gas flow rate experimental results show that a split ratio of 1:1 to 10:1 can produce chromatographic results that meet the analytical requirements. A carrier gas flow rate of 1.0 ml / min causes a baseline rise, interfering with the solvent detection at 9.388 min and preventing solvent content detection. However, a carrier gas flow rate of 2.0 to 3.0 ml / min can produce chromatographic results that meet the analytical requirements.

[0105] Example 7

[0106] This example examines various residual solvents in the drug portion of the ADC (compound of Formula I).

[0107] The compound of formula I is the compound of Example 15 in patent publication number WO2018113652, and is primarily used to treat chronic hepatitis B. Five solvents, methanol, ethyl acetate, acetonitrile, dichloromethane, and toluene, are used in the production process of the compound.

[0108] 1. Chromatographic conditions

[0109] The chromatographic conditions were the same as in Example 1

[0110] 2. Solution Preparation

[0111] Preparation of test solution: Take about 0.1 g of the ADC drug portion (compound of formula I, batch 01), accurately weigh it, place it in an empty bottle, accurately add 1 ml of N-methylpyrrolidone, and seal it to use as the test solution.

[0112] Preparation of Reference Solution 1: Accurately weigh appropriate amounts of methanol, acetonitrile, dichloromethane, ethyl acetate, and toluene. Dilute with N-methylpyrrolidone to a solution containing approximately 0.3 mg of methanol, 0.041 mg of acetonitrile, 0.06 mg of dichloromethane, 0.5 mg of ethyl acetate, and 0.089 mg of toluene per 1 ml. Accurately measure 1 ml into a 20 ml headspace vial and seal.

[0113] 3. Determination method:

[0114] Accurately measure the blank solution, reference solution 1 and test solution, inject them into the headspace respectively, and record the chromatograms.

[0115] Calculation formula: calculated by peak area according to the external standard method.

[0116] Where: W std1 is the sample amount of the solvent in the reference solution 1, mg;

[0117] A spl is the peak area of ​​the solvent in the test solution;

[0118] DF spl is the dilution factor of the test solution;

[0119] W spl is the sample weight of the test sample, mg;

[0120] AvgA std1 is the average peak area of ​​the solvent in reference solution 1 for 5 consecutive measurements;

[0121] DF std1 is the dilution multiple of reference solution 1.

[0122] 4. Measurement results

[0123] The determination results were calculated by peak area according to the external standard method. See Table 11, and the chromatograms are shown in Figures 2-4, which are chromatogram 2 of blank solvent, chromatogram 3 of reference solution 1, and chromatogram 4 of test solution Formula I compound batch 01.

[0124] Table 11 Determination of residual solvents in compounds of formula I

[0125] Example 8

[0126] This example examines various residual solvents in the drug portion of the ADC (compound of Formula II).

[0127] Compound II, described in Example 5 of patent publication number WO2019184744, is a white to yellow solid primarily used to prevent and treat thromboembolic diseases. Twelve solvents were used in the production process: methanol, ethanol, isopropanol, acetonitrile, dichloromethane, tert-butyl methyl ether, ethyl acetate, tetrahydrofuran, n-heptane, 1,4-dioxane, toluene, and N,N-dimethylformamide.

[0128] 1. Chromatographic conditions

[0129] The chromatographic conditions were the same as in Example 1

[0130] 2. Solution Preparation

[0131] Preparation of test solution: Take about 0.1 g of the ADC drug part (compound of formula II), accurately weigh it, place it in an empty bottle, accurately add 1 ml of N-methylpyrrolidone, seal it, and use it as the test solution.

[0132] Two batches of Formula II compounds 01 and 02 were prepared into test solutions according to the above method, affixed with batch labels, and then tested.

[0133] Preparation of Reference Solution 2: Accurately weigh appropriate amounts of methanol, ethanol, isopropanol, acetonitrile, dichloromethane, tert-butyl methyl ether, ethyl acetate, tetrahydrofuran, n-heptane, 1,4-dioxane, toluene, and N,N-dimethylformamide. Dilute with N-methylpyrrolidone to a solution containing approximately 300 μg of methanol, 500 μg of ethanol, 500 μg of isopropanol, 41 μg of acetonitrile, 60 μg of dichloromethane, 500 μg of tert-butyl methyl ether, 500 μg of ethyl acetate, 72 μg of tetrahydrofuran, 500 μg of n-heptane, 38 μg of 1,4-dioxane, 89 μg of toluene, and 88 μg of N,N-dimethylformamide per 1 ml. Accurately measure 1 ml and place in an empty headspace vial. Seal the vial to serve as the reference solution.

[0134] 3. Determination method:

[0135] The determination method is the same as that in Example 7.

[0136] 4. Measurement results

[0137] The results were calculated using the external standard method using the peak area. See Table 12.

[0138] Table 12 Determination of residual solvents in compounds of formula II

Claims

1. A gas chromatography analysis method for simultaneously detecting multiple residual solvents in a drug, characterized in that: The gas chromatography conditions were as follows: Inlet temperature: 200-250°C; preferably 230°C; Column box heating program: initial column temperature is 30-40°C, preferably 35°C, maintained for 6-10 min, preferably 8-10 min, heated to 220°C at a rate of 15-25°C per minute, preferably heated to 220°C at a rate of 15-20°C per minute, maintained for 3-7 min, preferably 5-7 min.

2. The analysis method according to claim 1, characterized in that The sample to be tested needs to be diluted with a diluent before injection, and the diluent is N-methylpyrrolidone.

3. The analysis method according to any one of claims 1 or 2, characterized in that The chromatographic column used in the analytical method is a medium polarity or non-polar capillary chromatographic column.

4. The analysis method according to claim 3, characterized in that The medium polarity capillary chromatographic column is a capillary chromatographic column using 6% cyanopropylphenyl-94% dimethylpolysiloxane as a stationary liquid, preferably a VF624 capillary chromatographic column.

5. The analysis method according to claim 3, characterized in that The non-polar capillary chromatographic column is a capillary chromatographic column with 100% dimethyl polysiloxane as the stationary liquid, preferably an HP-1 capillary chromatographic column.

6. The analysis method according to any one of claims 1 to 5, characterized in that The carrier gas flow rate in the gas chromatograph is 2.0-3.0 ml / min.

7. The analysis method according to any one of claims 1 to 6, characterized in that The injection mode of the analysis method is split injection, and the split ratio is 1-10:1, preferably the split ratio is 5-10:

1.

8. The analysis method according to any one of claims 1 to 7, characterized in that The headspace equilibrium temperature of the analytical method is greater than 70°C, preferably 70-90°C.

9. The analysis method according to any one of claims 1 to 8, characterized in that The analytical method can be used to detect a variety of residual solvents, which are one or more combinations of methanol, tetrahydrofuran, ethanol, cyclohexane, ether, isopropyl acetate, acetone, n-heptane, isopropanol, n-butanol, acetonitrile, dioxane, dichloromethane, pyridine, tert-butanol, toluene, tert-butyl methyl ether, N,N-dimethylformamide, n-hexane, dimethyl sulfoxide and ethyl acetate.

10. The analysis method according to any one of claims 1 to 9, characterized in that: The drug is a biological targeted drug or a chemical targeted drug; preferably, the biological targeted drug is one or more of a monoclonal antibody, a biclonal antibody, and an antibody-drug conjugate (ADC).

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