Method for determining readily oxidizable substances in rubber plug water extract

Abstract

The invention relates to the technical field of detection of readily oxidizable substances in a water extract of a rubber plug, in particular to a method for determining the readily oxidizable substances in the water extract of the rubber plug. The method specifically comprises the following steps: firstly, carrying out high-pressure sterilization treatment on a rubber plug-water solution filled into a Schottky bottle through a high-pressure sterilizer, filling a rubber plug water extract subjected to the high-pressure sterilization treatment into a TOC (Total Organic Carbon) sampling bottle, and carrying out total organic carbon determination on the rubber plug water extract by using a total organic carbon determination instrument according to a total organic carbon determination method. According to the method provided by the invention, the problem that the readily oxidizable substances in the rubber plug water extract are not quantitatively measured in the prior art is solved, the limitation of a previous method for calculating a difference value by a titration method is changed, and the accuracy and the working efficiency of measuring the readily oxidizable substances in the rubber plug water extract can be improved. Meanwhile, by means of the method, volatile and non-volatile readily oxidizable substances in the water extracting solution of the rubber plug can be monitored, and the heat stability of the rubber plug can be further reflected.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of detection of easily oxidizable substances in water extract of rubber stopper, and particularly relates to a method for determining easily oxidizable substances in water extract of rubber stopper. BACKGROUND

[0002] Rubber stopper for injection of halogenated butyl rubber and rubber stopper for pre-filled syringe of chlorinated butyl rubber are the most commonly used rubber inner packaging materials in the pharmaceutical industry. Because they are directly in contact with drugs and are high molecular materials, their quality stability is particularly important. The quality control items thereof include physical items (such as insoluble particles, self-sealing property and puncture chipping, etc.), chemical items (such as infrared identification, pH of water extract, heavy metals, conductivity and easily oxidizable substances, etc.) and biological items (hemolysis, acute toxicity, etc.). Among them, the determination of easily oxidizable substances in the chemical detection item of the water extract of the rubber stopper is to determine the easily oxidizable organic substances contained in the water solution of the rubber stopper after high-pressure sterilization treatment, including rubber oligomers and volatile and non-volatile organic substances.

[0003] At present, the determination of easily oxidizable substances in the chemical detection item of the water extract of the rubber stopper is to add potassium permanganate oxidant to the solution and then use sodium thiosulfate titrant to titrate and reduce the easily oxidizable substances in the solution, and the results are compared by the difference between the blank solution and the sample solution. This method needs to prepare potassium permanganate solution, dilute sulfuric acid solution and sodium thiosulfate titrant, the process is complicated, the results are not quantified, the error is large and the efficiency is too low.

[0004] Therefore, it is urgent to obtain a new method for determining easily oxidizable substances in the water extract of the rubber stopper to solve the above problems. SUMMARY

[0005] The present application provides a method for determining easily oxidizable substances in the water extract of the rubber stopper. The method provided by the present application solves the problem that the easily oxidizable substances in the water extract of the rubber stopper are not quantitatively determined in the related art, changes the limitation of the previous difference value determination method, and can improve the accuracy and work efficiency of the determination of the easily oxidizable substances in the water extract of the rubber stopper. At the same time, the method of the present application can monitor the volatile and non-volatile easily oxidizable substances in the water extract of the rubber stopper, and further reflect the heat stability of the rubber stopper.

[0006] In the present application, the rubber stopper-water solution contained in a Schott bottle is subjected to high-pressure sterilization treatment by a high-pressure sterilizer, and then the rubber stopper water extract and the blank solution after high-pressure sterilization treatment are loaded into a 40ml TOC sample bottle matched with a total organic carbon determinator and subjected to total organic carbon determination.

[0007] The principle of the total organic carbon analyzer is as follows: based on advanced membrane conductivity detection technology, through the use of ultraviolet radiation and chemical oxidant (ammonium persulfate), the carbon in the organic compounds in the solution is oxidized to CO2, through a selective gas permeable membrane, CO2 can pass through the membrane to the deionized water provided by the instrument DI end loop system, CO2 reacts with water to form carbonic acid, which can be decomposed into hydrogen ions and bicarbonate ions, which are measured by a conductivity cell. The measured conductivity result is converted into carbon content to accurately determine the total organic carbon content in the solution.

[0008] Because a large amount of easily oxidizable substances will be precipitated after the autoclaving of the rubber stopper aqueous solution, the composition is relatively complex. Therefore, the total organic carbon determination method is used to determine the organic impurities in the rubber stopper aqueous solution after autoclaving, which solves the technical deficiencies of the original sodium thiosulfate titration method, such as complicated operation, large error and inability to quantify, etc.

[0009] The principle of the total organic carbon analyzer is based on advanced membrane conductivity detection technology, which can accurately detect the total carbon content and inorganic carbon content in the rubber stopper aqueous extract, and the total organic carbon content can be obtained by the difference between the total carbon content and the inorganic carbon content, which can accurately reflect the content of the easily oxidizable impurities in the rubber stopper aqueous extract.

[0010] The autoclave can realize programmed temperature rise and fall, and accurately control the rubber stopper autoclaving process,

[0011] The Schott bottle is made of medium borosilicate glass material, which is used to contain the rubber stopper to be autoclaved and will not cause adverse effects such as precipitates on the aqueous extract.

[0012] The 40ml TOC sample bottle is suitable for the total organic carbon analyzer, and the background TOC is controlled to be less than 10ppb after strict cleaning.

[0013] The application provides a method for determining the easily oxidizable substances in the rubber stopper aqueous extract, which adopts the following technical scheme:

[0014] A method for determining the easily oxidizable substances in the rubber stopper aqueous extract, which specifically comprises the following steps: first, the rubber stopper-aqueous solution in the Schott bottle is autoclaved by the autoclave, the rubber stopper aqueous extract after autoclaving is filled into the TOC sample bottle, and the total organic carbon determination of the rubber stopper aqueous extract is carried out by the total organic carbon analyzer according to the total organic carbon determination method.

[0015] Optionally, the high temperature treatment condition is 121±2℃ for 20-30min.

[0016] Optionally, the total organic carbon analyzer is a Sievers M9 TOC analyzer.

[0017] Optionally, the total organic carbon determination method is total organic carbon determination by using a Sievers M9 TOC analyzer according to the principle of total organic carbon determination.

[0018] Optionally, before the high-temperature treatment, the rubber plug is pretreated, and the pretreatment specifically comprises: taking the complete rubber plug into a conical flask, submerging in ultrapure water, boiling for 3-5 min, cooling, and then repeatedly washing with 400 mL of ultrapure water for 5 times.

[0019] Optionally, the limit standard of the method is that the total organic carbon is less than or equal to 1.5 ppm.

[0020] In summary, the present application includes at least one of the following beneficial technical effects:

[0021] The present application performs high-pressure sterilization treatment on the rubber plug-water solution in a Schott bottle by using an autoclave, then the rubber plug water extract and the blank solution after high-pressure sterilization treatment are loaded into a 40 ml TOC sample bottle matched with a total organic carbon determination instrument and total organic carbon determination is performed. The autoclave can realize programmed temperature rise and fall. The Schott bottle containing the rubber plug water extract is made of stable medium borosilicate glass material and will not precipitate other impurities. The 40 ml TOC sample bottle is strictly cleaned and the TOC background is controlled to be less than 10 ppb. The Sievers M9 TOC analyzer can accurately determine the total organic carbon content in the rubber plug water extract by using an advanced thin film conductivity detection technology, so as to quantify the easily oxidizable substances in the rubber plug water extract.

[0022] The method provided by the present application solves the problem that the easily oxidizable substances in the rubber plug water extract are not quantitatively determined in the related art, changes the limitation of the previous titration method difference value method, and can improve the accuracy and work efficiency of the determination of the easily oxidizable substances in the rubber plug water extract. At the same time, the method of the present application can monitor the easily volatile and non-volatile easily oxidizable substances in the water extract of the rubber plug, and further reflects the heat stability of the rubber plug. BRIEF DESCRIPTION OF DRAWINGS

[0023] Figure 1 The photo of the autoclave used in the determination method provided by the present application.

[0024] Figure 2 The photo of the Sievers M9 TOC analyzer used in the determination method provided by the present application.

[0025] Figure 3 The scene diagram of the Schott bottle used in the determination method provided by the present application.

[0026] Figure 4 The scene diagram of the 40 ml TOC sample bottle used in the determination method provided by the present application. DETAILED DESCRIPTION

[0027] Before describing embodiments of the application in detail, it is to be understood that the terminology used herein is for the purpose of describing particular embodiments only. Unless otherwise defined, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art to which this application pertains.

[0028] It should be noted that the terms "first", "second" are used only for the purpose of description, and cannot be understood as indicating or implying relative importance or implicitly indicating the number of the technical features indicated. Therefore, the features defined with "first", "second" can explicitly or implicitly include one or more of the features. Further, in the description of the present application, unless otherwise stated, the meaning of "a plurality of" is two or more.

[0029] The endpoints of the ranges and any values disclosed herein are not limited to the precise values stated. The ranges or values should be construed to be roughly about the ranges or values. For ranges of values, the endpoints of the ranges are included, between the endpoints of the ranges, between the endpoints of the ranges and individual points within the ranges, and between individual points within the ranges, new ranges can be taken, which should be considered to be specifically disclosed herein.

[0030] In the present application, the term "comprising" or "including" is an open-ended expression, i.e. including what is indicated in the present application, but not excluding other aspects.

[0031] In order to make the purpose, technical solutions and advantages of the present application clearer, the technical solutions in the embodiments of the present application will be described clearly and completely. Based on the embodiments of the present application, all other embodiments obtained by those skilled in the art without creative labor are within the scope of protection of the present application. The embodiments described below are exemplary and are used to explain the present application, and cannot be understood as limiting the present application.

[0032] Unless otherwise specified, the technical or conditions in the embodiments are carried out according to the techniques or conditions described in the literature in the art or according to the product manual. Unless otherwise specified, the reagents or instruments used are conventional products that can be obtained from the market.

[0033] The present application will be further described in detail below in combination with the embodiments and the accompanying drawings.

[0034] Example 1

[0035] The present embodiment provides a method for determining the easily oxidizable substances in the water extract of rubber plug. The following is described in detail.

[0036] The method needs to use an autoclave, a total organic carbon analyzer, a Schott bottle and a TOC sample bottle. The autoclave is specifically as follows Figure 1As shown in the figure, the Schott bottle scene diagram is specifically as shown in Figure 3 In this embodiment, the total organic carbon analyzer is specifically a Sievers M9 TOC analyzer, specifically as shown in Figure 2 As shown in the figure, the TOC sample bottle is specifically a 40ml TOC sample bottle, specifically as shown in Figure 4

[0037] The autoclave can realize programmed heating and cooling, and accurately control the autoclave process of the plug.

[0038] The principle of the total organic carbon analyzer is as follows: based on advanced membrane conductivity detection technology, by using ultraviolet radiation and chemical oxidant (ammonium persulfate), the carbon of organic compounds in the solution is oxidized to CO2, through a selective gas permeable membrane, CO2 can pass through the membrane to the deionized water provided by the instrument DI end loop system, CO2 reacts with water to form carbonic acid, and carbonic acid reacts with water to decompose into hydrogen ions and bicarbonate ions, which are measured by a conductivity cell. Other molecules are intercepted in the sample end.

[0039] The Schott bottle is made of medium borosilicate glass, which is used to hold the plug to be autoclaved, and will not cause adverse effects on the precipitates in the water extract.

[0040] The 40ml TOC sample bottle is suitable for the total organic carbon analyzer, and the field is strictly cleaned and controlled to have a TOC background of less than 10ppb.

[0041] The above method specifically includes the following steps: first, the plug-water solution loaded in the Schott bottle is autoclaved by the autoclave, the plug water extract after autoclaving is loaded into the 40ml TOC sample bottle, and the total organic carbon of the plug water extract is determined by the Sievers M9 TOC analyzer according to the total organic carbon determination method.

[0042] This method solves the problem that the easily oxidizable substances in the plug water extract are not quantitatively determined, changes the previous titration method, and improves the accuracy and work efficiency of the determination of easily oxidizable substances in the plug water extract.

[0043] The working principle of the above method is as follows:

[0044] First, the plug water extract is prepared, and the specific method is: take 200cm 2 ​The complete rubber stopper 34 (according to the rubber stopper surface area calculation of the number of rubber stopper used) was immersed in a conical flask with 400 mL of ultrapure water, boiled for 5 min, cooled, then washed with 400 mL of ultrapure water, a total of 5 times, i.e. 400 mL of ultrapure water was repeatedly washed 5 times. After each washing, the washing liquid was discarded. The rubber stopper was placed in a Schott bottle, and 400 mL of ultrapure water was added. After covering the bottle opening with aluminum foil, it was placed in an autoclave at 121 ℃ (121 ℃ ± 2 ℃) for 30 min, cooled to room temperature, removed, and the solution was the rubber stopper water extract; and at the same time, a blank solution (ultrapure water was autoclaved under the same conditions as the sample solution to obtain the blank solution) was prepared for standby.

[0045] Then the rubber stopper water extract and the blank solution were respectively rinsed with 2 40 ml TOC sample bottles for 3 times, and the rubber stopper water extract and the blank solution were respectively loaded into the TOC sample bottles. The total organic carbon of the rubber stopper water extract was determined by Sievers M9 TOC analyzer according to the total organic carbon determination method.

[0046] The test results are shown in Table 1.

[0047] Table 1 Determination results of rubber stopper water extract and blank solution

[0048]

[0049] From the determination results in Table 1, the value of the rubber stopper water extract of bromobutyl rubber for freeze-drying injection by the easy oxidizable substance titration method (sodium thiosulfate titration solution) is 0.2 mL, and the value of the total organic carbon determination method is 1.378 ppm; the value of the rubber stopper water extract of chlorobutyl rubber for pre-filled syringe by the easy oxidizable substance titration method (sodium thiosulfate titration solution) is 0.2 mL, and the value of the total organic carbon determination method is 0.913 ppm.

[0050] In summary, the method for determining the easy oxidizable substance in the rubber stopper water extract by the total organic carbon determination method provided in the application is feasible, and it is recommended to use 1.5 ppm of total organic carbon as the limit standard of easy oxidizable substance.

[0051] In the method for determining the easy oxidizable substance in the rubber stopper water extract by the total organic carbon determination method provided in the application, the boiling and washing of the rubber stopper are both simulated according to the specific use in production. The incoming rubber stopper needs to be cleaned and sterilized before being used for preparation production.

[0052] In the description of the specification, the description of the terms "one embodiment", "some embodiments", "example", "specific example" or "some examples" etc. means that the specific features, structures, materials or characteristics described in connection with the embodiment or example are contained in at least one embodiment or example of the present application. In the description of the specification, the illustrative description of the above terms does not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any appropriate manner in any one or more embodiments or examples. In addition, those skilled in the art can combine and combine the different embodiments or examples described in the specification and the features of the different embodiments or examples without contradiction.

[0053] Finally, it should be noted that: the above embodiments are only used to illustrate the technical solutions of the present application, and not to limit them; although the present application has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that: it can still modify the technical solutions recorded in the foregoing embodiments, or make equivalent replacement for part of the technical features; and these modifications or replacements do not make the essence of the corresponding technical solution deviate from the spirit and scope of the technical solutions of the embodiments of the present application.

Claims

1. A method for determining oxidizable substances in a rubber stopper water extract, characterized in that: The method specifically includes the following steps: firstly, a rubber stopper-water solution loaded into a Schott bottle is subjected to high-pressure sterilization by an autoclave, the rubber stopper water extract after high-pressure sterilization is loaded into a TOC injection bottle, and the total organic carbon of the rubber stopper water extract is measured by a total organic carbon analyzer according to the total organic carbon determination method.

2. The method according to claim 1, characterized in that The high temperature treatment condition is: maintaining at 121±2°C for 20-30 min.

3. The method according to claim 1, wherein The total organic carbon analyzer is a Sievers M9 TOC analyzer.

4. The method according to claim 1, wherein The total organic carbon determination method is to use a Sievers M9TOC analyzer to perform total organic carbon determination according to the total organic carbon determination principle.

5. The method according to claim 1, wherein Before the high-temperature treatment, the rubber stopper is pretreated. The pretreatment is as follows: a complete rubber stopper is placed in a conical flask, immersed in ultrapure water, boiled for 3-5 minutes, cooled, and then rinsed with 400 mL of ultrapure water for 5 times.

6. The method according to claim 1, characterized in that The limiting standard of the method is total organic carbon ≤ 1.5 ppm.

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