Quality detection method of halogenated butyl rubber plug for sterile powder for injection

Abstract

The invention discloses a quality detection method of a halogenated butyl rubber plug for sterile powder for an injection. The halogenated butyl rubber plug for the sterile powder for the injection is quantitatively detected aiming at seven highly toxic organic matters. Comprising the following steps: preparing five extracting solutions for extracting sterile powder for injection by using a halogenated butyl rubber plug; the invention relates to a liquid chromatography-mass spectrometry detection method and a toxicological evaluation method for seven highly toxic organic matters. According to the method disclosed by the invention, the seven highly toxic organic matters in the sterile powder halogenated butyl rubber plug for injection are correspondingly detected, so that the compatibility of the halogenated butyl rubber plug for the sterile powder for injection and the medicine can be evaluated, and the safety of packaging materials of the medicine and related preparations of the medicine can be ensured.

Description

Technical Field

[0001] The invention belongs to the field of detection technology, in particular to a quality detection method for a halogenated butyl rubber plug for sterile powder for injection. Background Art

[0002] Sterile powder for injection, commonly known as powder injection, refers to the raw material drug or sterile powder or sterile block made with suitable excipients for preparation into injection solution with sterile solution before clinical use.

[0003] The quality requirements for sterile powder for injection are very strict. In addition to complying with the various provisions of the Chinese Pharmacopoeia for raw materials for injection, they must also meet the following requirements:

[0004] 1. The powder has no foreign matter, and after being made into solution, the foreign matter can be seen and the inspection is qualified;

[0005] 2. The powder fineness or crystallinity should be suitable for easy packaging;

[0006] 3. Sterile and pyrogen-free;

[0007] 4. For freeze-dried products, they should be complete blocks or sponges, with full appearance and no shrinkage, uniform color, dry, good porosity, and can quickly return to the state before freeze-drying by adding water;

[0008] 5. Insoluble particles, filling volume difference, content uniformity, etc. comply with regulations.

[0009] Halogenated butyl rubber plug is a key component widely used in many fields. Halogenated butyl rubber plug is synthesized from halogenated butyl rubber and vulcanizing agent and other chemical raw materials. Halogenated butyl rubber (HI IR) is the product of butyl rubber reacting with chlorine or bromine in aliphatic hydrocarbon solvents. It can be divided into two categories: chlorinated butyl rubber (CI IR) and brominated butyl rubber (BI IR).

[0010] Halogenated butyl rubber stoppers are valued for their unique properties and wide range of applications. They can be used to seal injections and other pharmaceutical preparations to ensure the safety and effectiveness of drugs.

[0011] In order to ensure that the quality of halogenated butyl rubber stoppers meets the relevant standards and requirements, strict testing is required. This is related to the safety and effectiveness of sterile powder drugs. Strict testing of halogenated butyl rubber stoppers is required to ensure that halogenated butyl rubber stoppers will not release harmful substances during use. Through testing, potential quality problems can be effectively identified and risks in the drug production process can be reduced.

[0012] The invention provides a quality detection method for a halogenated butyl rubber stopper for sterile powder for injection to solve the corresponding problem. Summary of the invention

[0013] The purpose of the present invention is to provide a quality detection method for a halogenated butyl rubber stopper for sterile powder for injection, so as to solve the deficiencies in the prior art.

[0014] The technical solution adopted by the present invention is as follows:

[0015] A quality testing method for halogenated butyl rubber stoppers for sterile powders for injection, which quantitatively tests halogenated butyl rubber stoppers for seven highly toxic organic substances;

[0016] The specific method includes the following steps:

[0017] The reference substance stock solution was diluted step by step with methanol, and the sample was injected and measured under the established determination conditions. The concentration of the reference substance stock solution corresponding to the peak intensity of 3 times the signal-to-noise ratio was taken as the detection limit, and the MRM graph was recorded. The concentration of the reference substance stock solution corresponding to the peak intensity of 10 times the signal-to-noise ratio was taken as the quantitative limit.

[0018] Take the test solution and reference substance stock solution, and perform the test according to the established test conditions and methods;

[0019] Record the chromatogram and calculate the content Ci of each component in the sample test solution by external standard method;

[0020]

[0021] Ci: concentration of each component in the test sample, μg / ml;

[0022] Cs: concentration of each component in the reference substance, μg / ml;

[0023] Ai: peak area of ​​test product;

[0024] As: reference peak area;

[0025] f: unit conversion factor.

[0026] As a further technical solution: the 7 highly toxic organic substances are:

[0027] Benzothiazole, 2-mercaptobenzothiazole, tetramethylthiuram disulfide, diphenylamine, dimethylamine, aniline, triphenylphosphine oxide.

[0028] As a further technical solution: the preparation method of the reference substance stock solution is:

[0029] Accurately weigh 10 mg of each reference substance of 2-mercaptobenzothiazole, tetramethylthiuram disulfide, diphenylamine, and triphenylphosphine oxide, place in a 50 ml volumetric flask, add methanol to dissolve and dilute to the scale, and shake well; accurately measure 8 μl of benzothiazole reference substance and 10 μl of aniline reference substance, place in a 50 ml volumetric flask, add methanol to dissolve and dilute to the scale, and shake well; accurately measure 200 μl of dimethylamine reference substance, place in a 10 ml volumetric flask, add methanol to dissolve and dilute to the scale, and shake well;

[0030] Accurately measure 50 μl of the above-mentioned mixed solution of 2-mercaptobenzothiazole, tetramethylthiuram disulfide, diphenylamine, and triphenylphosphine oxide, 50 μl of the mixed solution of benzothiazole and aniline, and 50 μl of the dimethylamine solution, place them in the same 20 ml volumetric flask, add methanol to dilute to the scale, and shake well to obtain the reference substance stock solution;

[0031] Among them, the concentrations of 2-mercaptobenzothiazole, tetramethylthiuram disulfide, diphenylamine, aniline, triphenylphosphine oxide, benzothiazole, and dimethylamine were all 500 μg / L solution.

[0032] As a further technical solution: the predetermined measurement conditions are:

[0033] Ion source: electrospray ion source;

[0034] Scan polarity: positive ion scan;

[0035] Scanning mode: multiple reaction detection;

[0036] Capillary voltage: 3.5kv;

[0037] Ion source temperature: 150°C;

[0038] Desolventization temperature: 450°C;

[0039] Desolvation gas flow rate: 800L / Hr;

[0040] BEHC18 column: 2.1×100mm, 1.7μm;

[0041] Mobile phase: methanol-water solution containing 0.1% formic acid and 5 mmol ammonium acetate, with a volume ratio of ethanolamine to water of 60:40;

[0042] Injection volume: 2 μl;

[0043] Column temperature: 40°C;

[0044] Flow rate: 0.3ml / min.

[0045] As a further technical solution: the test solution comprises:

[0046] Extract A and blank extract A, extract B and blank extract B, extract C and blank extract C, extract D and blank extract D, extract E and blank extract E;

[0047] The extraction solvent used in the corresponding extraction is selected from any one of extraction solvent A, extraction solvent B, extraction solvent C, extraction solvent D, and extraction solvent E;

[0048] The extraction solvent A is an acidic buffer solution; the pH of the 0.2 mol / L NaCl solution is adjusted to 2.5 with 1 mol / L HCl;

[0049] The extraction solvent B is an alkaline buffer solution; the pH of the 0.1 mol / L Na2HPO4 solution is adjusted to 10.0 with 1 mol / L HCl;

[0050] The extraction solvent C is a blank preparation solution without active ingredients;

[0051] The extraction solvent D is an ethanol solution; anhydrous ethanol and water are mixed in a mass ratio of 1:1;

[0052] The extraction solvent E is methanol.

[0053] As a further technical solution: the preparation methods of the extract A and the blank extract A are respectively:

[0054] Weigh 25g of halogenated butyl rubber stopper, weigh accurately, place in 250ml solvent bottles, add 50ml extraction solvent A, place at 50℃ for 3 days, take out, cool to room temperature and use as extraction solution A;

[0055] At the same time, take 50 ml of extraction solvent A and perform the same operation as blank extraction solution A;

[0056] As a further technical solution: the preparation methods of the extract B and the blank extract B are respectively:

[0057] Weigh 25g of halogenated butyl rubber stopper, weigh accurately, place in 250ml solvent bottles, add 50ml extraction solvent B, place at 50℃ for 3 days, take out, cool to room temperature and use as extraction solution B;

[0058] At the same time, take 50 ml of extraction solvent B and perform the same operation as blank extraction solution B.

[0059] As a further technical solution: the preparation methods of the extract C and the blank extract C are respectively:

[0060] Weigh 25g of halogenated butyl rubber stopper, weigh accurately, place in 250ml solvent bottles, add 50ml extraction solvent C, place at 50℃ for 3 days, take out, cool to room temperature and use as extraction solution C;

[0061] At the same time, take 50 ml of extraction solvent C and perform the same operation as blank extraction solution C.

[0062] As a further technical solution: the preparation methods of the extract D and the blank extract D are respectively:

[0063] Weigh 25 g of halogenated butyl rubber stopper, weigh accurately, and place in 250 ml solvent bottles, add 50 ml of extraction solvent D, place at 50 ° C for 3 days, take out, and cool to room temperature as extraction solution D;

[0064] At the same time, take 50 ml of extraction solvent D and perform the same operation as blank extraction solution D.

[0065] As a further technical solution: the preparation methods of the extract E and the blank extract E are respectively:

[0066] Weigh 25 g of halogenated butyl rubber stoppers, weigh accurately, and place them in 250 ml solvent bottles, add 50 ml of extraction solvent E, place them at 50°C for 3 days, then take them out and cool them to room temperature as extraction solution E;

[0067] At the same time, take 50 ml of extraction solvent E and perform the same operation as blank extraction solution E.

[0068] Beneficial effects:

[0069] The method of the present invention can ensure that the halogenated butyl rubber stoppers for injection do not contain these 7 special organic substances by performing corresponding tests on 7 highly toxic organic substances in sterile powder halogenated butyl rubber stoppers for injection, including benzothiazole, 2-mercaptobenzothiazole, tetramethylthiuram disulfide, diphenylamine, dimethylamine, aniline, and triphenylphosphine oxide, so as to control the limited addition of the 7 highly toxic organic substances in such rubber stoppers and avoid greater safety risks.

[0070] If the halogenated butyl rubber stopper contains 7 special organic substances, which are quantitatively analyzed by the established quality detection method and exceed the toxicological evaluation index, the 7 highly toxic organic substances in the rubber stopper may migrate into the preparation, resulting in safety risks for the preparation. The detection method of the present invention can timely discover and avoid these problems, thereby ensuring the quality and safety of such rubber stoppers and related preparations.

[0071] Compared with the existing detection technology, the advantages of the present invention are mainly reflected in: through the preparation of reference stock solution and test solution with different extraction solvents, the detection and analysis are carried out under specific measurement conditions, thereby increasing the quantitativeness of the halogenated butyl rubber stopper in the test process and making the detection more accurate.

[0072] The detection method of the present invention can enable enterprises to promptly discover and solve problems in halogenated butyl rubber plug materials, thereby improving the overall quality and reliability of the products.

[0073] Through the detection method of the present invention, a strict quality control system can be established, and the reliable detection results obtained can enhance consumers' trust and satisfaction with the product, thereby improving the company's brand image and market competitiveness.

[0074] In summary, the method of the present invention can significantly improve the detection accuracy of halogenated butyl rubber stoppers and reduce errors, which is of great significance for ensuring the quality and safety of such rubber stoppers and preparations, protecting patient health, enhancing product competitiveness, and promoting technological innovation and development. BRIEF DESCRIPTION OF THE DRAWINGS

[0075] Figure 1 MRM diagram of the reference stock solution;

[0076] Figure 1 Triphenylphosphine oxide (first row, left), tetramethylthiuram disulfide (first row, left second), diphenylamine (first row, left third), 2-mercaptobenzothiazole (second row, left first), benzothiazole (second row, left second), aniline (second row, left third), dimethylamine (third row, left first) (Note: the order is the same in Figures 2-11);

[0077] Figure 2 The MRM diagrams of triphenylphosphine oxide, tetramethylthiuram disulfide, diphenylamine, 2-mercaptobenzothiazole, benzothiazole, aniline, and dimethylamine in blank extract A;

[0078] Figure 3 The MRM diagrams of triphenylphosphine oxide, tetramethylthiuram disulfide, diphenylamine, 2-mercaptobenzothiazole, benzothiazole, aniline and dimethylamine in the halogenated butyl rubber plug extract A;

[0079] Figure 4 The MRM diagrams of triphenylphosphine oxide, tetramethylthiuram disulfide, diphenylamine, 2-mercaptobenzothiazole, benzothiazole, aniline, and dimethylamine in blank extract B;

[0080] Figure 5 The MRM diagrams of triphenylphosphine oxide, tetramethylthiuram disulfide, diphenylamine, 2-mercaptobenzothiazole, benzothiazole, aniline and dimethylamine in the halogenated butyl rubber plug extract B;

[0081] Figure 6 The MRM diagrams of triphenylphosphine oxide, tetramethylthiuram disulfide, diphenylamine, 2-mercaptobenzothiazole, benzothiazole, aniline, and dimethylamine in blank extract C;

[0082] Figure 7The MRM diagrams of triphenylphosphine oxide, tetramethylthiuram disulfide, diphenylamine, 2-mercaptobenzothiazole, benzothiazole, aniline and dimethylamine in the halogenated butyl rubber plug extract C;

[0083] Figure 8 The MRM diagrams of triphenylphosphine oxide, tetramethylthiuram disulfide, diphenylamine, 2-mercaptobenzothiazole, benzothiazole, aniline, and dimethylamine in blank extract D;

[0084] Fig. 9 The MRM diagrams of triphenylphosphine oxide, tetramethylthiuram disulfide, diphenylamine, 2-mercaptobenzothiazole, benzothiazole, aniline and dimethylamine in the halogenated butyl rubber plug extract D;

[0085] Fig.10 The MRM diagrams of triphenylphosphine oxide, tetramethylthiuram disulfide, diphenylamine, 2-mercaptobenzothiazole, benzothiazole, aniline, and dimethylamine in blank extract E;

[0086] Fig.11 This is the MRM chart of triphenylphosphine oxide, tetramethylthiuram disulfide, diphenylamine, 2-mercaptobenzothiazole, benzothiazole, aniline and dimethylamine in the halogenated butyl rubber plug extract E;. DETAILED DESCRIPTION

[0087] In order to enable those skilled in the art to better understand the solution of the present application, the technical solution in the embodiments of the present application will be clearly and completely described below in conjunction with the drawings in the embodiments of the present application. Obviously, the described embodiments are only part of the embodiments of the present application, not all of the embodiments. Based on the embodiments in the present application, all other embodiments obtained by ordinary technicians in this field without creative work should fall within the scope of protection of the present application.

[0088] Instruments: Waters ACQU I TY ultra-high performance liquid chromatograph, Xevo TQ-S micro triple quadrupole mass spectrometer, and MassLynx V4.2 data workstation.

[0089] Extraction solvent:

[0090] The extraction solvent A is an acidic buffer solution; the pH of the 0.2 mol / L NaCl solution is adjusted to 2.5 with 1 mol / L HCl;

[0091] Extraction solvent B is an alkaline buffer solution; 0.1 mol / L Na2HPO4 solution is adjusted to pH 10.0 with 1 mol / L HCl;

[0092] Extraction solvent C is: blank preparation solution without active ingredient;

[0093] The blank formulation solution without active ingredients is made of distilled water or physiological saline. The following examples use distilled water.

[0094] The extraction solvent D is an ethanol solution; anhydrous ethanol and water are mixed in a mass ratio of 1:1;

[0095] The extraction solvent E is methanol;

[0096] Methanol was chromatographic grade; source: Merck;

[0097] Anhydrous ethanol was chromatographically pure; source: Concord;

[0098] The water was ultrapure water;

[0099] Toxicology data calculation:

[0100] According to the Carcinogenicity Database (CPDB), the TD50 of MBT is 344 mg / (kg·d) (rat). The acceptable intake of MBT is calculated to be 0.344 mg / d [344 mg / (kg·d)÷50000×50 kg]. Based on the structural similarity between benzothiazole and dithiobenzothiazole, the PDE value of 344 μg / d can be used for safety assessment of benzothiazole and dithiobenzothiazole.

[0101] Referring to "Theory and Practice of Drug and Packaging Compatibility", it can be known that the PDE value of diphenylamine in injectable preparations is 600μg / d. Based on the structural similarity between aniline and diphenylamine, the PDE value of 600μg / d can be used for safety assessment of aniline.

[0102] Consider referring to the Cramer classification (using the Toxtree software established by the European Chemicals Agency to classify chemicals into Cramer structures) to determine the threshold: divided into Cramer I, II, and III. Class I: 1800 μg / d; Class II: 540 μg / d; Class III: 90 μg / d. Tetramethylthiuram disulfide, dimethylamine, and triphenylphosphine oxide all belong to Cramer III, and the PDE value of 90 μg / d is used for safety assessment.

[0103] The weight of the halogenated butyl rubber stopper is approximately 0.469 g per piece. According to the sample supplier, the maximum daily dosage of the sterile powder is 1 bottle.

[0104] According to the formula AET = PDE ÷ (1 bottle / day × component weight / bottle) * uncertainty (50%) or AET = PDE ÷ (1 bottle / day × component weight / bottle) ÷ extraction solution volume (ml / g) ÷ pretreatment dilution factor * uncertainty (50%), the AET values ​​were calculated respectively. The results are shown in Table 2.

[0105] The following are specific embodiments

[0106] Example 1

[0107] A quality testing method for halogenated butyl rubber stoppers for sterile powders for injection, which quantitatively tests halogenated butyl rubber stoppers for seven highly toxic organic substances;

[0108] The specific method includes the following steps:

[0109] The reference substance stock solution was diluted step by step with methanol, and the sample was injected and measured under the established determination conditions. The concentration of the reference substance stock solution corresponding to the peak intensity of 3 times the signal-to-noise ratio was taken as the detection limit, and the MRM graph was recorded. The concentration of the reference substance stock solution corresponding to the peak intensity of 10 times the signal-to-noise ratio was taken as the quantitative limit.

[0110] Take the test solution and reference substance stock solution, and perform the test according to the established test conditions and methods;

[0111] Record the chromatogram and calculate the content Ci of each component in the sample test solution by external standard method;

[0112]

[0113] Ci: concentration of each component in the test sample, μg / ml;

[0114] Cs: concentration of each component in the reference substance, μg / ml;

[0115] Ai: peak area of ​​test product;

[0116] As: reference peak area;

[0117] f: unit conversion factor.

[0118] The 7 highly toxic organic substances are:

[0119] Benzothiazole, 2-mercaptobenzothiazole, tetramethylthiuram disulfide, diphenylamine, dimethylamine, aniline, triphenylphosphine oxide.

[0120] The preparation method of reference substance stock solution is as follows:

[0121] Accurately weigh 10 mg of each reference substance of 2-mercaptobenzothiazole, tetramethylthiuram disulfide, diphenylamine, and triphenylphosphine oxide, place in a 50 ml volumetric flask, add methanol to dissolve and dilute to the scale, and shake well; accurately measure 8 μl of benzothiazole reference substance and 10 μl of aniline reference substance, place in a 50 ml volumetric flask, add methanol to dissolve and dilute to the scale, and shake well; accurately measure 200 μl of dimethylamine reference substance, place in a 10 ml volumetric flask, add methanol to dissolve and dilute to the scale, and shake well;

[0122] Accurately measure 50 μl of the above-mentioned mixed solution of 2-mercaptobenzothiazole, tetramethylthiuram disulfide, diphenylamine, and triphenylphosphine oxide, 50 μl of the mixed solution of benzothiazole and aniline, and 50 μl of the dimethylamine solution, place them in the same 20 ml volumetric flask, add methanol to dilute to the scale, and shake well to obtain the reference substance stock solution;

[0123] Among them, the concentrations of 2-mercaptobenzothiazole, tetramethylthiuram disulfide, diphenylamine, aniline, triphenylphosphine oxide, benzothiazole, and dimethylamine were all 500 μg / L solution.

[0124] The established measurement conditions are:

[0125] Ion source: electrospray ion source;

[0126] Scan polarity: positive ion scan;

[0127] Scanning mode: multiple reaction detection;

[0128] Capillary voltage: 3.5kv;

[0129] Ion source temperature: 150°C;

[0130] Desolventization temperature: 450°C;

[0131] Desolvation gas flow rate: 800L / Hr;

[0132] BEHC18 column: 2.1×100mm, 1.7μm;

[0133] Mobile phase: methanol-water solution containing 0.1% formic acid and 5 mmol ammonium acetate, with a volume ratio of ethanolamine to water of 60:40;

[0134] Injection volume: 2 μl;

[0135] Column temperature: 40°C;

[0136] Flow rate: 0.3ml / min.

[0137] Test solution:

[0138] Extract A and blank extract A;

[0139] The extraction solvent used in the corresponding extraction is selected as extraction solvent A;

[0140] The extraction solvent A was an acidic buffer solution; the pH of the 0.2 mol / L NaCl solution was adjusted to 2.5 with 1 mol / L HCl.

[0141] The preparation methods of extract A and blank extract A are:

[0142] Weigh 25g of halogenated butyl rubber stopper, weigh accurately, place in 250ml solvent bottles, add 50ml extraction solvent A, place at 50℃ for 3 days, take out, cool to room temperature and use as extraction solution A;

[0143] At the same time, take 50 ml of extraction solvent A and perform the same operation as blank extraction solution A;

[0144] Example 2

[0145] Based on Example 1, the difference is as follows: Test solution:

[0146] Extract B and blank extract B;

[0147] The extraction solvent used in the corresponding extraction is selected as extraction solvent B;

[0148] Extraction solvent B is an alkaline buffer solution; 0.1 mol / L Na2HPO4 solution is adjusted to pH 10.0 with 1 mol / L HCl;

[0149] The preparation methods of extract B and blank extract B are:

[0150] Weigh 25g of halogenated butyl rubber stopper, weigh accurately, place in 250ml solvent bottles, add 50ml extraction solvent B, place at 50℃ for 3 days, take out, cool to room temperature and use as extraction solution B;

[0151] At the same time, take 50 ml of extraction solvent B and perform the same operation as blank extraction solution B. The rest of the technical solution remains unchanged.

[0152] Example 3

[0153] Based on Example 1, the difference is as follows: Test solution:

[0154] Extract C and blank extract C;

[0155] The extraction solvent used in the corresponding extraction is selected as extraction solvent C;

[0156] The extraction solvent C is a blank preparation solution without active ingredients;

[0157] The preparation methods of extract C and blank extract C are:

[0158] Weigh 25g of halogenated butyl rubber stopper, weigh accurately, place in 250ml solvent bottles, add 50ml extraction solvent C, place at 50℃ for 3 days, take out, cool to room temperature and use as extraction solution C;

[0159] At the same time, take 50 ml of extraction solvent C and perform the same operation as blank extraction solution C. The rest of the technical scheme remains unchanged.

[0160] Example 4

[0161] Based on Example 1, the difference is as follows: Test solution:

[0162] Extract D and blank extract D;

[0163] The extraction solvent used in the corresponding extraction is selected as extraction solvent D;

[0164] The extraction solvent D is an ethanol solution; anhydrous ethanol and water are mixed in a mass ratio of 1:1;

[0165] The preparation methods of extract D and blank extract D are:

[0166] Weigh 25 g of halogenated butyl rubber stopper, weigh accurately, and place in 250 ml solvent bottles, add 50 ml of extraction solvent D, place at 50 ° C for 3 days, take out, and cool to room temperature as extraction solution D;

[0167] At the same time, take 50 ml of extraction solvent D and perform the same operation as blank extraction solution D. The rest of the technical solution remains unchanged.

[0168] Example 5

[0169] Based on Example 1, the difference is as follows: Test solution:

[0170] Extract E and blank extract E;

[0171] The extraction solvent used in the corresponding extraction is selected as extraction solvent E;

[0172] The extraction solvent E is methanol;

[0173] The preparation methods of extract E and blank extract E are:

[0174] Weigh 25 g of halogenated butyl rubber stoppers, weigh accurately, and place them in 250 ml solvent bottles, add 50 ml of extraction solvent E, place them at 50°C for 3 days, then take them out and cool them to room temperature as extraction solution E;

[0175] At the same time, take 50 ml of extraction solvent E and perform the same operation as blank extraction solution E. The rest of the technical scheme remains unchanged.

[0176] test:

[0177] Specific indicators of benzothiazole, 2-mercaptobenzothiazole, tetramethylthiuram disulfide, diphenylamine, dimethylamine, aniline, and triphenylphosphine oxide are shown in Table 1:

[0178] Table 1

[0179]

[0180] Table 2 PDE and AET values ​​of 7 highly toxic organic compounds

[0181]

[0182] Note: The volume of the extraction solution is 2 ml / g, and the pre-treatment dilution factor is 0;

[0183] Table 4 Quantitative test results of 7 highly toxic organic compounds for halogenated butyl rubber stoppers for injection

[0184]

[0185] Note: ND means not detected.

[0186] Benzothiazole, 2-mercaptobenzothiazole, tetramethylthiuram disulfide, diphenylamine, dimethylamine, aniline, and triphenylphosphine oxide are listed in the "Technical Guidelines for Compatibility Studies of Chemicals and Elastomer Seals (Trial)" as "extractables that may need to be focused on in seal materials (but not limited to)", and need to be focused on. After testing, benzothiazole, 2-mercaptobenzothiazole, tetramethylthiuram disulfide, diphenylamine, dimethylamine, aniline, and triphenylphosphine oxide were not detected in the halogenated butyl rubber stoppers for injection under the above five extraction solvents at 50°C for 3 days.

[0187] The MRM diagram of the reference stock solution is shown in Figure 1 The MRM diagrams of triphenylphosphine oxide, tetramethylthiuram disulfide, diphenylamine, 2-mercaptobenzothiazole, benzothiazole, aniline, and dimethylamine in the blank and halogenated butyl rubber plug extracts of different extraction solvents are shown in Figure 2-Figure 11 .

[0188] The above description is only a preferred embodiment of the present invention, but the present invention is not limited to the scope of implementation shown. Any changes made in accordance with the concept of the present invention, or modifications to equivalent embodiments with equivalent changes, which still do not exceed the spirit covered by the specification, should be within the protection scope of the present invention.

Claims

1. A quality inspection method for halogenated butyl rubber stoppers for sterile powder for injection, characterized in that: Quantitative detection of halogenated butyl rubber stoppers for seven highly toxic organic compounds; The specific method includes the following steps: The reference substance stock solution was diluted step by step with methanol, and the sample was injected and measured under the established determination conditions. The concentration of the reference substance stock solution corresponding to the peak intensity of 3 times the signal-to-noise ratio was taken as the detection limit, and the MRM graph was recorded. The concentration of the reference substance stock solution corresponding to the peak intensity of 10 times the signal-to-noise ratio was taken as the quantitative limit. Take the test solution and reference substance stock solution, and perform the test according to the established test conditions and methods; Record the chromatogram and calculate the content Ci of each component in the sample test solution by external standard method; Ci: concentration of each component in the test sample, μg / ml; Cs: concentration of each component in the reference substance, μg / ml; Ai: peak area of ​​test product; As: reference peak area; f: unit conversion factor.

2. The quality inspection method for a halogenated butyl rubber stopper for sterile powder for injection according to claim 1, characterized in that: The 7 highly toxic organic substances are: Benzothiazole, 2-mercaptobenzothiazole, tetramethylthiuram disulfide, diphenylamine, dimethylamine, aniline, triphenylphosphine oxide.

3. The quality inspection method for a halogenated butyl rubber stopper for sterile powder for injection according to claim 2, characterized in that: The preparation method of the reference substance stock solution is: Accurately weigh 10 mg of each reference substance of 2-mercaptobenzothiazole, tetramethylthiuram disulfide, diphenylamine, and triphenylphosphine oxide, place in a 50 ml volumetric flask, add methanol to dissolve and dilute to the scale, and shake well; accurately measure 8 μl of benzothiazole reference substance and 10 μl of aniline reference substance, place in a 50 ml volumetric flask, add methanol to dissolve and dilute to the scale, and shake well; accurately measure 200 μl of dimethylamine reference substance, place in a 10 ml volumetric flask, add methanol to dissolve and dilute to the scale, and shake well; Accurately measure 50 μl of the above-mentioned mixed solution of 2-mercaptobenzothiazole, tetramethylthiuram disulfide, diphenylamine, and triphenylphosphine oxide, 50 μl of the mixed solution of benzothiazole and aniline, and 50 μl of the dimethylamine solution, place them in the same 20 ml volumetric flask, add methanol to dilute to the scale, and shake well to obtain the reference substance stock solution; Among them, the concentrations of 2-mercaptobenzothiazole, tetramethylthiuram disulfide, diphenylamine, aniline, triphenylphosphine oxide, benzothiazole, and dimethylamine were all 500 μg / L solution.

4. The quality inspection method for a halogenated butyl rubber stopper for sterile powder for injection according to claim 3, characterized in that: The established measurement conditions are: Ion source: electrospray ion source; Scan polarity: positive ion scan; Scanning mode: multiple reaction detection; Capillary voltage: 3.5kv; Ion source temperature: 150°C; Desolventization temperature: 450°C; Desolvation gas flow rate: 800L / Hr; BEHC18 column: 2.1×100mm, 1.7μm; Mobile phase: methanol-water solution containing 0.1% formic acid and 5 mmol ammonium acetate, with a volume ratio of ethanolamine to water of 60:40; Injection volume: 2 μl; Column temperature: 40°C; Flow rate: 0.3ml / min.

5. The quality inspection method for a halogenated butyl rubber stopper for sterile powder for injection according to claim 1, characterized in that: The test solution comprises: One of extract A and blank extract A, extract B and blank extract B, extract C and blank extract C, extract D and blank extract D, extract E and blank extract E; The extraction solvent used in the corresponding extraction is selected from any one of extraction solvent A, extraction solvent B, extraction solvent C, extraction solvent D, and extraction solvent E; The extraction solvent A is an acidic buffer solution; the pH of the 0.2 mol / L NaCl solution is adjusted to 2.5 with 1 mol / L HCl; The extraction solvent B is an alkaline buffer solution; the pH of the 0.1 mol / L Na2HPO4 solution is adjusted to 10.0 with 1 mol / L HCl; The extraction solvent C is a blank preparation solution without active ingredients; The extraction solvent D is an ethanol solution; anhydrous ethanol and water are mixed in a mass ratio of 1:1; The extraction solvent E is methanol.

6. The quality inspection method for a halogenated butyl rubber stopper for sterile powder for injection according to claim 5, characterized in that: The preparation methods of the extract A and blank extract A are respectively: Weigh 25g of halogenated butyl rubber stopper, weigh accurately, place in 250ml solvent bottles, add 50ml extraction solvent A, place at 50℃ for 3 days, take out, cool to room temperature and use as extraction solution A; At the same time, take 50 ml of extraction solvent A and perform the same operation as blank extraction solution A.

7. The quality inspection method for a halogenated butyl rubber stopper for sterile powder for injection according to claim 5, characterized in that: The preparation methods of the extract B and blank extract B are respectively: Weigh 25g of halogenated butyl rubber stopper, weigh accurately, place in 250ml solvent bottles, add 50ml extraction solvent B, place at 50℃ for 3 days, take out, cool to room temperature and use as extraction solution B; At the same time, take 50 ml of extraction solvent B and perform the same operation as blank extraction solution B.

8. The quality inspection method for a halogenated butyl rubber stopper for sterile powder for injection according to claim 5, characterized in that: The preparation methods of the extract C and the blank extract C are respectively: Weigh 25g of halogenated butyl rubber stopper, weigh accurately, place in 250ml solvent bottles, add 50ml extraction solvent C, place at 50℃ for 3 days, take out, cool to room temperature and use as extraction solution C; At the same time, take 50 ml of extraction solvent C and perform the same operation as blank extraction solution C.

9. The quality inspection method for a halogenated butyl rubber stopper for sterile powder for injection according to claim 5, characterized in that: The preparation methods of the extract D and the blank extract D are respectively: Weigh 25 g of halogenated butyl rubber stopper, weigh accurately, and place in 250 ml solvent bottles, add 50 ml of extraction solvent D, place at 50 ° C for 3 days, take out, and cool to room temperature as extraction solution D; At the same time, take 50 ml of extraction solvent D and perform the same operation as blank extraction solution D.

10. The quality inspection method for a halogenated butyl rubber stopper for sterile powder for injection according to claim 5, characterized in that: The preparation methods of the extract E and the blank extract E are respectively: Weigh 25 g of halogenated butyl rubber stoppers, weigh accurately, and place them in 250 ml solvent bottles, add 50 ml of extraction solvent E, place them at 50°C for 3 days, then take them out and cool them to room temperature as extraction solution E; At the same time, take 50 ml of extraction solvent E and perform the same operation as blank extraction solution E.

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