Headspace gas chromatography detection method for simultaneously determining multiple residual solvents in pharmaceutical adjuvant hydroxypropyl methylcellulose

Abstract

The invention discloses a headspace gas chromatography detection method for simultaneously determining multiple residual solvents in pharmaceutical adjuvant hydroxypropyl methylcellulose. The headspace gas chromatography detection method comprises the following steps: preparing a reference solution containing the residual solvents; preparing a test solution of hydroxypropyl methylcellulose; respectively injecting the reference solution and the test solution into a headspace gas chromatograph for testing, and calculating the content of each residual solvent by peak area according to an external standard method; through accurate control of gas chromatography conditions, the method can accurately, rapidly and simultaneously detect the contents of residual methanol, isopropanol, dichloromethane, trichloromethane, benzene, trichloroethylene, dioxane and toluene in the pharmaceutical adjuvant hydroxypropyl methylcellulose, and has the advantages of simplicity and convenience in operation, high accuracy and sensitivity, good reproducibility and the like.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical excipient detection, and particularly relates to a headspace gas chromatography detection method for simultaneously determining multiple residual solvents in the pharmaceutical excipient hypromellose. Background Art

[0002] Pharmaceutical excipients are an important part of pharmaceutical preparations, and their quality directly affects the clinical effectiveness and safety of pharmaceutical preparations. Hydroxypropyl methylcellulose (HPMC) is a non-ionic ether derivative of cellulose obtained by partial methylation and partial polyhydroxypropylation through processes such as alkalization, etherification, neutralization and washing. It has the advantages of cold water solubility, reaction inertness, strong anti-allergy, metabolic inertness, acid-base stability, and good film-forming properties. It is widely used as a multifunctional pharmaceutical excipient.

[0003] With the further advancement of the pharmaceutical excipients related review work, the market demand for HPMC as a commonly used cellulose ether pharmaceutical excipient is increasing. Detecting and controlling safety indicators such as solvent residues in HPMC is of great significance for the production of high-quality pharmaceutical excipient HPMC.

[0004] The production process of HPMC used as a pharmaceutical excipient includes a slurry method and a hot water dissolution method. Among them, the domestic production process of HPMC is basically a one-step slurry method. The toluene-isopropanol-water mixed system is mainly used. After the crushed refined cotton is added to the mixed system, it is produced by reacting with propylene oxide and methyl chloride under the action of alkali. A mixed gas of toluene and isopropanol, and side reaction products of methyl chloride and propylene oxide will be produced during the production process. A variety of solvents such as toluene and isopropanol are used in this production process. Hydroxypropyl methylcellulose products may contain a variety of residual solvents, which poses a safety hazard to related pharmaceutical preparations using this product. In the production process of HPMC, the second-class solvent toluene and the third-class solvent isopropanol, which should be restricted in use according to the 2020 edition of the "Chinese Pharmacopoeia", may also contain methanol, dichloromethane, chloroform, benzene, trichloroethylene and dioxane and other residual solvents.

[0005] However, the 2020 edition of the "Chinese Pharmacopoeia" has not yet set up an inspection item for solvent residues in the pharmaceutical excipient hypromellose. There are defects and deficiencies in the quality control of the pharmaceutical excipient hypromellose, and it is necessary to establish an appropriate residual solvent detection method for the pharmaceutical excipient hypromellose. Summary of the invention

[0006] In order to solve the above technical problems, the present invention provides a headspace gas chromatography detection method for simultaneously determining multiple residual solvents in the pharmaceutical excipient hypromellose, and the headspace gas chromatography detection method is used to simultaneously realize the quantitative detection of eight residual solvents in the pharmaceutical excipient hypromellose.

[0007] The technical solution adopted by the present invention is as follows:

[0008] A headspace gas chromatography detection method for simultaneously determining multiple residual solvents in pharmaceutical excipient hypromellose, the detection method comprising the following steps:

[0009] (1) preparing a reference solution containing residual solvent;

[0010] (2) preparing a test solution of hypromellose;

[0011] (3) Inject the reference solution and the test solution into a headspace gas chromatograph for testing, and calculate the content of each residual solvent by peak area using the external standard method;

[0012] The chromatographic conditions of headspace gas chromatography were:

[0013] Column temperature: programmed temperature rise, initial temperature 38-42°C, hold for 4-6 min, then raise the temperature to 155-165°C at a rate of 3-7°C / min, hold for 0.8-1.2 min; then raise the temperature to 225-235°C at a rate of 30-40°C / min, hold for 0.8-1.2 min;

[0014] Headspace conditions: headspace bottle heating temperature: 88-92°C; equilibration time 15-25 min, injection time 0.8-1.2 min.

[0015] The residual solvents are methanol, isopropanol, dichloromethane, chloroform, benzene, trichloroethylene, dioxane and toluene.

[0016] Furthermore, the chromatographic conditions of the headspace gas chromatograph are preferably as follows: column temperature: programmed temperature rise, initial temperature 40°C, maintained for 5 min, and heated to 160°C at a rate of 5°C / min, maintained for 1 min; then heated to 230°C at a rate of 35°C / min, maintained for 1 min; headspace conditions: headspace bottle heating temperature: 90°C; equilibration time: 20 min; injection time: 1 min.

[0017] The chromatographic column of the headspace gas chromatograph is a DB-624 quartz capillary column, and the stationary liquid is 6 wt % cyanopropylphenyl and 94 wt % dimethylsiloxane.

[0018] The carrier gas of the headspace gas chromatograph is nitrogen, and the carrier gas flow rate is 1.8 to 2.2 mL / min, preferably 2 mL / min.

[0019] The injection port temperature of the headspace gas chromatograph is 245-255° C.; the injection mode is split injection, and the split ratio is 3-6:1, preferably 5:1.

[0020] The detector of the headspace gas chromatograph is a hydrogen flame ionization detector, and the FID temperature is 245 to 255°C, preferably 250°C.

[0021] In step (1), in the reference solution, the final concentrations of methanol, isopropanol, dichloromethane, chloroform, benzene, trichloroethylene, dioxane, and toluene are 300 μg / mL, 500 μg / mL, 60 μg / mL, 6 μg / mL, 0.2 μg / mL, 8 μg / mL, 38 μg / mL, and 89 μg / mL, respectively; and the solvent is a 50% volume concentration of dimethyl sulfoxide aqueous solution.

[0022] In step (2), the preparation method of the test solution of hydroxypropyl methylcellulose is: dissolving hydroxypropyl methylcellulose and anhydrous sodium sulfate in a 50% volume concentration of dimethyl sulfoxide aqueous solution to make the final concentration of hydroxypropyl methylcellulose 40 mg / mL.

[0023] The mass ratio of hydroxypropyl methylcellulose and anhydrous sodium sulfate is 1:5. The addition of anhydrous sodium sulfate can improve the sensitivity of detection.

[0024] In order to solve the defect of lacking solvent residual inspection items in the current national standard analysis method of pharmaceutical excipient hypromellose, the present invention establishes a headspace gas chromatography detection method for simultaneously determining 8 kinds of residual solvents methanol, isopropanol, dichloromethane, chloroform, benzene, trichloroethylene, dioxane and toluene in pharmaceutical excipient hypromellose. The detection method is simple to operate and has accurate results, which provides a scientific basis for improving the quality standard of pharmaceutical excipient hypromellose.

[0025] In this method, the detection limits of methanol, isopropanol, dichloromethane, chloroform, benzene, trichloroethylene, dioxane, and toluene are 0.041 μg·mL -1 , 0.069μg·mL -1 , 0.014μg·mL -1 , 0.004μg·mL -1 , 0.002μg·mL -1 , 0.008μg·mL -1 , 0.071 μg·mL -1 , 0.004μg·mL -1 .

[0026] In this method, the limits of quantification of methanol, isopropanol, dichloromethane, chloroform, benzene, trichloroethylene, dioxane, and toluene are 0.138 μg·mL -1 , 0.230μg·mL -1 , 0.051 μg·mL -1 , 0.015μg·mL -1 , 0.007μg·mL-1 , 0.032 μg·mL -1 , 0.238 μg·mL -1 , 0.013μg·mL -1 .

[0027] Compared with the prior art, the present invention has the following beneficial effects:

[0028] The invention develops a detection method for residual solvents in pharmaceutical excipient hypromellose, which can provide a good scientific basis for enterprises to control the quality of the product.

[0029] The detection method provided by the present invention can detect 8 residual solvents in hypromellose at one time, thereby improving the detection efficiency.

[0030] The detection method provided by the present invention supplements the technical method for detecting residual solvents in pharmaceutical excipients in the 2020 edition of the "Chinese Pharmacopoeia", thereby improving the product quality of related enterprises. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 is the gas chromatogram of blank solvent;

[0032] Figure 2 The gas chromatogram of the reference substance solution in Example 1;

[0033] Figure 3 It is the gas chromatogram of the test solution in Example 1;

[0034] Figure 4 The gas chromatogram of the reference substance solution in Comparative Example 1;

[0035] Figure 5 The gas chromatogram of the reference substance solution in Comparative Example 1;

[0036] Figure 6 The gas chromatogram of the reference substance solution in Comparative Example 1;

[0037] Figure 7 The gas chromatogram of the reference substance solution in Comparative Example 1;

[0038] Figure 8 The gas chromatogram of the reference substance solution in Comparative Example 1;

[0039] Fig. 9 This is the gas chromatogram of the test sample plus the mixed reference solution in Test Example 1. DETAILED DESCRIPTION

[0040] The present invention is described in detail below with reference to the embodiments.

[0041] The headspace gas chromatograph used in the examples is an Agilent 6890 gas chromatograph, and an Agilent G1888 headspace injector is used.

[0042] Chromatographic column: DB-624 elastic quartz capillary column (the stationary liquid is 6% cyanopropylphenyl-94% dimethylsiloxane; 30m×0.530mm, 3.00μm);

[0043] Column temperature: programmed temperature rise, initial temperature 40°C, hold for 5 min, then increase to 160°C at a rate of 5°C / min, hold for 1 min; then increase to 230°C at a rate of 35°C / min, hold for 1 min;

[0044] Carrier gas: high-purity nitrogen; flow rate: 2mL / min;

[0045] Inlet temperature: 250°C;

[0046] The injection mode was split injection with a split ratio of 5:1;

[0047] Detector: hydrogen flame ionization detector, FID temperature: 250°C;

[0048] Headspace conditions: headspace bottle heating temperature: 90°C; equilibration time: 20 min; injection time: 1 min.

[0049] Example 1

[0050] A headspace gas chromatography detection method for simultaneously determining multiple residual solvents in pharmaceutical excipient hypromellose, the detection method comprising the following steps:

[0051] (1) Preparation of reference substance solution: Methanol, isopropanol, dichloromethane, chloroform, benzene, trichloroethylene, dioxane and toluene are placed in the same brown volumetric flask and diluted with a 50% volume concentration of dimethyl sulfoxide aqueous solution to prepare a mixed reference substance stock solution. The mixed reference substance stock solution is then transferred and diluted with a 50% volume concentration of dimethyl sulfoxide aqueous solution to prepare a mixed reference substance intermediate solution. The mixed reference substance intermediate solution is transferred and diluted with a 50% volume concentration of dimethyl sulfoxide aqueous solution to prepare a mixed The reference substance working solution, in which the final concentrations of methanol, isopropanol, dichloromethane, chloroform, benzene, trichloroethylene, dioxane and toluene are 300μg / mL, 500μg / mL, 60μg / mL, 6μg / mL, 0.2μg / mL, 8μg / mL, 38μg / mL and 89μg / mL, respectively; 5mL of the mixed reference substance working solution was measured and placed in a 20mL headspace injection vial, 1.0g of anhydrous sodium sulfate was added, the solution was sealed and shaken to obtain the reference substance solution.

[0052] (2) Preparation of a test solution of hydroxypropyl methylcellulose: Weigh 0.2 g of the pharmaceutical excipient hydroxypropyl methylcellulose, add 1.0 g of anhydrous sodium sulfate into a 20-mL headspace injection bottle, add 5 mL of a 50% volume concentration of dimethyl sulfoxide aqueous solution, seal, and shake to obtain the test solution. The final concentration of hydroxypropyl methylcellulose in the solution is 40 mg / mL.

[0053] (3) Using 50% volume concentration of dimethyl sulfoxide aqueous solution as solvent, single solutions with the following final concentrations were prepared: 0.3 mg / mL methanol, 0.5 mg / mL isopropanol, 0.06 mg / mL dichloromethane, 0.006 mg / mL chloroform, 0.0002 mg / mL benzene, 0.008 mg / mL trichloroethylene, 0.038 mg / mL dioxane, and 0.089 mg / mL toluene.

[0054] (4) injecting each single solution in step (3) into a headspace gas chromatograph for testing, and locating the peak positions of methanol, isopropanol, dichloromethane, chloroform, benzene, trichloroethylene, dioxane, and toluene;

[0055] (5) The blank solvent, reference solution, and test solution were injected into a headspace gas chromatograph for testing. The blank solvent was a 50% volume concentration of dimethyl sulfoxide aqueous solution. The gas chromatogram was as shown in FIG. Figure 1 The gas chromatogram of the reference solution is shown in Figure 2 The gas chromatogram of the test solution is shown in Figure 3 As shown, the content of each residual solvent is calculated by peak area according to the external standard method. The calculation formula is shown in (1):

[0056]

[0057] Where: wt%—mass percentage of residual solvent;

[0058] A x —The peak area of ​​the corresponding residual solvent peak in the test solution;

[0059] A s —Peak area of ​​the corresponding residual solvent peak in the reference solution;

[0060] C s —Concentration of the corresponding residual solvent in the reference solution (mg / mL);

[0061] V—the dilution volume of the test solution (mL);

[0062] W—Weighed mass of the test sample (mg).

[0063] from Figure 1It can be seen that the blank solvent has no interference with the test and reference solutions. Figure 2 It can be seen that under the test conditions of this embodiment, the separation of the 8 solvent peaks in the reference solution is good and complete, the separation R is greater than 1.5, and the peak symmetry is good.

[0064] Comparative Example 1

[0065] The other conditions are the same as in Example 1, except that the conditions of the headspace gas chromatograph are changed to:

[0066] Column temperature: programmed temperature rise, initial temperature 45°C, maintained for 6 min, run for 6 min; then raised to 220°C at a rate of 25°C / min, run for 15 min;

[0067] The injection mode was splitless injection;

[0068] Headspace conditions: headspace bottle heating temperature: 85°C; equilibration time: 30 min; injection time: 0.2 min.

[0069] The gas chromatogram of the reference solution is as follows: Figure 4 As shown in the figure, it can be seen that under the test conditions of this comparative example, the 8 solvent peaks in the reference solution cannot be completely separated.

[0070] Comparative Example 2

[0071] The other conditions are the same as in Example 1, except that the conditions of the headspace gas chromatograph are changed to:

[0072] Column temperature: initial temperature 55°C, maintained for 6 min; then raised to 200°C at a rate of 35°C / min, maintained for 6 min;

[0073] Carrier gas: high purity nitrogen; flow rate: 1mL / min;

[0074] Inlet temperature: 200°C;

[0075] The injection mode was split injection with a split ratio of 1:1;

[0076] Headspace conditions: headspace bottle heating temperature: 85°C; equilibration time: 30 min; injection time: 1 min.

[0077] The gas chromatogram of the reference solution is as follows: Figure 5 As shown in the figure, it can be seen that under the test conditions of this comparative example, the 8 solvent peaks in the reference solution cannot be completely separated.

[0078] Comparative Example 3

[0079] The other conditions are the same as in Example 1, except that the conditions of the headspace gas chromatograph are changed to:

[0080] Column temperature: Initial temperature 40°C, maintain for 5 min; then increase the temperature to 220°C at a rate of 15°C / min, maintain for 2 min;

[0081] The injection mode was split injection with a split ratio of 2:1;

[0082] Headspace conditions: headspace bottle heating temperature: 85°C; equilibration time: 30 min; injection time: 0.2 min.

[0083] The gas chromatogram of the reference solution is as follows: Figure 6 As shown in the figure, it can be seen that under the test conditions of this comparative example, the 8 solvent peaks in the reference solution cannot be completely separated.

[0084] Comparative Example 4

[0085] The other conditions are the same as in Example 1, except that the conditions of the headspace gas chromatograph are changed to:

[0086] Column temperature: programmed temperature rise, initial temperature 40°C, hold for 8 min; increase to 180°C at a rate of 3°C / min, hold for 1 min; then increase to 230°C at a rate of 20°C / min, hold for 2 min;

[0087] The injection mode was split injection with a split ratio of 4:1;

[0088] Headspace conditions: headspace bottle heating temperature: 85°C; equilibration time: 30 min; injection time: 0.2 min.

[0089] The gas chromatogram of the reference solution is as follows: Figure 7 As shown, under the chromatographic conditions in this comparative example, the separation of the chromatographic peaks of each component is improved, and the chromatographic peaks of the last several components are completely separated, but the chromatographic peaks of the first several components cannot be completely separated, the peaks are split, and the chromatographic analysis time is long.

[0090] Comparative Example 5

[0091] The other conditions are the same as in Example 1, except that the conditions of the headspace gas chromatograph are changed to:

[0092] Column temperature: programmed temperature rise, initial temperature 35°C, hold for 8 min; increase the temperature to 160°C at a rate of 3°C / min, hold for 2 min; then increase the temperature to 230°C at a rate of 20°C / min, hold for 5 min;

[0093] The injection mode was split injection with a split ratio of 3:1;

[0094] Headspace conditions: headspace bottle heating temperature: 85°C; equilibration time: 30 min; injection time: 0.2 min.

[0095] The gas chromatogram of the reference solution is as follows: Figure 8 As shown in the figure, it can be seen that under the chromatographic conditions in this comparative example, the separation of the chromatographic peaks of each component is improved, and the chromatographic peaks of the later components are completely separated, but the earlier chromatographic peaks are split, such as the methanol peak splitting, the isopropanol and dichloromethane peaks have shoulder peaks, and the chromatographic analysis time is relatively long.

[0096] Test Example 1 Specificity Test

[0097] 0.2 g of hydroxypropyl methylcellulose test sample and 1.0 g of anhydrous sodium sulfate were added to 5 mL of the reference solution prepared in Example 1 to obtain a mixed solution, which was injected into a headspace gas chromatograph for testing. The conditions of the headspace gas chromatograph were the same as those in Example 1. The gas chromatogram was as shown in FIG. Fig. 9 As shown in the figure, it can be seen that the addition of the test sample of HPMC will not have any effect on the peak position and peak area of ​​each solvent in the reference solution.

[0098] Test Example 2 Linear Test

[0099] Preparation of linear solution (the linear solution contains 8 solvents at the same time): the concentration range of the linear solution is from the quantitative limit of the residual solvent to 150% of the concentration of the reference solution, which are 12 concentration levels: 1%, 2.5%, 5.0%, 10%, 20%, 50%, 100%, 150%, 200%, 250%, 500% and 1000%. Taking dichloromethane in the solution as an example, its linear concentration levels are: 0.6328, 1.582, 3.164, 6.328, 12.656, 31.640, 63.280, 94.920, 126.560, 158.200, 316.400 and 632.800 μg / mL, respectively. Other residual solvents are converted according to the proportion of the reference solution. 5.0 mL of each linear solution was transferred to a 20 mL headspace bottle and injected into the gas chromatograph using the headspace injection method. The chromatogram was recorded, and the solution concentration was used as the abscissa and the peak area value was used as the ordinate to plot the linear regression equation. The results are shown in Table 1. The results show that the linear correlation coefficients r of the eight residual solvents are between 0.9993 and 1.0000, and the linear relationship is good.

[0100] Test Example 3 Detection Limit and Quantification Limit

[0101] The signal-to-noise ratio S / N=3 was used as the detection limit, and the signal-to-noise ratio S / N=10 was used as the quantification limit. The results of the detection limit and quantification limit are shown in Table 1.

[0102] Table 1. Linear relationship determination results

[0103]

[0104] Wherein, Y represents the chromatographic peak area corresponding to each residual solvent, and X represents the concentration of each residual solvent (in μg / mL).

[0105] Test Example 4: Precision Test

[0106] Prepare a mixed reference solution and a mixed reference solution with the pharmaceutical excipient hydroxypropyl methylcellulose added (test sample spiked solution), draw 5.0mL into a 20mL headspace bottle, seal it, and take 6 samples in parallel. Continuously inject the headspace 6 times, record the peak area of ​​each residual solvent in the 6 injections, calculate the relative standard deviation, and the repeatability test results of the mixed reference solution and the repeatability test results of the test solution spiked are shown in Table 2 and Table 3, respectively. The results show that the relative standard deviation of the peak area of ​​8 residual solvents is no more than 3.0%, indicating that the precision of the instrument chromatography system is good, and the repeatability of the headspace gas chromatography method for the residual solvent of the pharmaceutical excipient hydroxypropyl methylcellulose is good. The intermediate precision of the validation method of the same batch of samples spiked with mixed solutions was measured by different operators on different days, and the relative standard deviations of the eight residual solvents were no more than 5.0%, indicating that the method has good precision.

[0107] Table 2 Precision test results of mixed reference solution

[0108]

[0109] Table 3 Repeatability test results of the test sample spiked solution

[0110]

[0111]

[0112] Test Example 5 Accuracy Test

[0113] According to the 2020 edition of the Chinese Pharmacopoeia 9101 Validation Guidelines for Analytical Methods, accuracy refers to the degree to which the result determined by the established method is close to the true value or reference value, generally expressed as recovery rate (%). Accuracy should be measured within the specified linear range.

[0114] Accurately weigh 200 mg of the test sample HPMC into a 20 mL headspace bottle, and add 5.0 mL of a mixed solution consisting of DMSO and water in a volume ratio of 1:1 as the blank solution.

[0115] In addition, 9 portions of the same test sample, 200 mg each, were accurately weighed, and each group of 3 portions was divided into 5 groups. 5.0 mL of linear solutions with concentrations of 50%, 100%, and 150% of the concentration of the residual solvent reference solution were pipetted from each group to dissolve them. The results were measured in sequence and the recovery was calculated according to the following formula. The results are shown in Table 5. The experimental results show that the recovery rates of the eight solvents are all within the range of 80% to 105%, and the RSD values ​​are all ≤4.0%, indicating that the accuracy of this method is good.

[0116] Recovery rate = (measured value of spiked sample - measured value of sample) ÷ spiked amount × 100%

[0117] The measured value of the spiked sample refers to the content of each residual solvent in the spiked sample, and the measured value of the sample refers to the content of the residual solvent in the unspiked sample.

[0118] The measured values ​​of the samples are all 0; the measured values ​​of the spiked samples are as shown in Table 4:

[0119] Table 4 Accuracy test spiked values

[0120]

[0121]

[0122] Table 5 Spiked recovery test results

[0123]

[0124]

[0125] Test Example 6: Stability Study

[0126] Accurately weigh 200 mg of the pharmaceutical excipient hydroxypropyl methylcellulose test sample into a 20 mL headspace bottle, add 5.0 mL of the mixed reference solution and a mixed solution consisting of DMSO and water in a volume ratio of 1:1, respectively, seal the bottle, and place it at room temperature for 0, 2, 4, 8, 12, and 24 h. Detection was performed in turn, and the peak area was recorded. The relative standard deviations of the peak areas of the eight residual solvents within 24 h were all less than 5.0%, indicating that the spiked solution of the test sample was basically stable within 24 h, and there was no obvious change trend in the spiked contents of the eight residual solvents.

[0127] The above-mentioned reference examples provide a detailed description of a headspace gas chromatography detection method for simultaneously determining multiple residual solvents in the pharmaceutical excipient hypromellose, which is illustrative rather than restrictive, and several embodiments can be listed according to the limited scope. Therefore, changes and modifications without departing from the overall concept of the present invention should fall within the scope of protection of the present invention.

Claims

1. A headspace gas chromatography method for simultaneously determining multiple residual solvents in pharmaceutical excipient hypromellose, characterized in that: The detection method comprises the following steps: (1) preparing a reference solution containing residual solvent; (2) preparing a test solution of hypromellose; (3) Inject the reference solution and the test solution into a headspace gas chromatograph for testing, and calculate the content of each residual solvent by peak area using the external standard method; The chromatographic conditions of headspace gas chromatography were: Column temperature: programmed temperature rise, initial temperature 38-42°C, hold for 4-6 min, then raise the temperature to 155-165°C at a rate of 3-7°C / min, hold for 0.8-1.2 min; then raise the temperature to 225-235°C at a rate of 30-40°C / min, hold for 0.8-1.2 min; Headspace conditions: headspace bottle heating temperature: 88-92°C; equilibration time 15-25 min, injection time 0.8-1.2 min.

2. The headspace gas chromatography detection method for simultaneously determining multiple residual solvents in the pharmaceutical excipient hypromellose according to claim 1, characterized in that: The residual solvents are methanol, isopropanol, dichloromethane, chloroform, benzene, trichloroethylene, dioxane and toluene.

3. The headspace gas chromatography detection method for simultaneously determining multiple residual solvents in the pharmaceutical excipient hypromellose according to claim 1, characterized in that: The chromatographic conditions of headspace gas chromatography were: Column temperature: programmed temperature, initial temperature 40°C, maintained for 5 min, then increased to 160°C at a rate of 5°C / min, maintained for 1 min; then increased to 230°C at a rate of 35°C / min, maintained for 1 min; Headspace conditions: headspace bottle heating temperature: 90°C; equilibration time: 20 min; injection time: 1 min.

4. The headspace gas chromatography detection method for simultaneously determining multiple residual solvents in the pharmaceutical excipient hypromellose according to claim 1, characterized in that: The chromatographic column of the headspace gas chromatograph is a DB-624 quartz capillary column, the stationary liquid is 6wt% cyanopropylphenyl and 94wt% dimethylsiloxane; the carrier gas is nitrogen, and the carrier gas flow rate is 1.8-2.2mL / min.

5. The headspace gas chromatography detection method for simultaneously determining multiple residual solvents in the pharmaceutical excipient hypromellose according to claim 1, characterized in that: The injection port temperature of the headspace gas chromatograph is 245-255°C; the injection mode is split injection, and the split ratio is 3-6:

1.

6. The headspace gas chromatography detection method for simultaneously determining multiple residual solvents in the pharmaceutical excipient hypromellose according to claim 1, characterized in that: The detector of the headspace gas chromatograph uses a hydrogen flame ionization detector, and the FID temperature is 245-255°C.

7. The headspace gas chromatography detection method for simultaneously determining multiple residual solvents in the pharmaceutical excipient hypromellose according to claim 1, characterized in that: In step (1), in the reference solution, the final concentrations of methanol, isopropanol, dichloromethane, chloroform, benzene, trichloroethylene, dioxane, and toluene are 300 μg / mL, 500 μg / mL, 60 μg / mL, 6 μg / mL, 0.2 μg / mL, 8 μg / mL, 38 μg / mL, and 89 μg / mL, respectively; and the solvent is a 50% volume concentration of dimethyl sulfoxide aqueous solution.

8. The headspace gas chromatography detection method for simultaneously determining multiple residual solvents in the pharmaceutical excipient hypromellose according to any one of claims 1 to 7, characterized in that: In step (2), the preparation method of the test solution of hydroxypropyl methylcellulose is: dissolving hydroxypropyl methylcellulose and anhydrous sodium sulfate in a 50% volume concentration of dimethyl sulfoxide aqueous solution to make the final concentration of hydroxypropyl methylcellulose 40 mg / mL.

9. The headspace gas chromatography detection method for simultaneously determining multiple residual solvents in the pharmaceutical excipient hypromellose according to claim 8, characterized in that: The mass ratio of hydroxypropyl methylcellulose to anhydrous sodium sulfate is 1:

5.

10. The headspace gas chromatography detection method for simultaneously determining multiple residual solvents in the pharmaceutical excipient hypromellose according to any one of claims 1 to 7, characterized in that: The detection limits of methanol, isopropanol, dichloromethane, chloroform, benzene, trichloroethylene, dioxane, and toluene are 0.041 μg·mL -1 , 0.069μg·mL -1 , 0.014μg·mL -1 , 0.004μg·mL -1 , 0.002μg·mL -1 , 0.008μg·mL -1 , 0.071 μg·mL -1 , 0.004μg·mL -1 .

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