A strong alkali resistant brominated butyl rubber stopper and its preparation method

Abstract

This invention relates to a brominated butyl rubber stopper resistant to strong alkalis, belonging to the field of medical rubber accessories, and provides a butyl rubber stopper for packaging strong alkali pharmaceutical preparations while possessing high purity. The stopper's formulation comprises, by weight ratio: brominated butyl rubber, butyl rubber, calcined kaolin, hydroxyapatite, sodium aluminum silicate, titanium dioxide, carbon black, stearic acid, magnesium oxide, vulcanizing agent, organic filler, and plasticizer. This brominated butyl rubber stopper uses a novel environmentally friendly carbon-nitrogen heterocyclic vulcanizing agent system, supplemented with strong alkali-resistant organic and inorganic fillers, exhibiting both good resistance to strong alkalis and excellent drug compatibility.

Description

Technical Field

[0001] This invention belongs to the field of medical rubber technology, specifically relating to a brominated butyl rubber stopper resistant to strong alkalis. Background Technology

[0002] Brominated butyl rubber, due to its excellent airtightness, chemical stability, low permeability, and good biocompatibility, has been widely used in pharmaceutical packaging stoppers for various injections and lyophilized powder injections. With the widespread clinical use of strongly alkaline drugs (such as proton pump inhibitors and alkaloid preparations), higher requirements have been placed on the tolerance of pharmaceutical stoppers in high pH environments.

[0003] Existing conventional brominated butyl rubber stoppers mostly employ traditional vulcanization systems and common filler formulations. Under prolonged contact with strongly alkaline drug solutions at pH 10 or higher, they are prone to problems such as cross-linking structure degradation, stopper swelling and deformation, and increased volume change rate. Simultaneously, some additives and fillers in the system are susceptible to migration or reaction with alkaline media, leading to particulate shedding, excessive dissolved substances, increased drug turbidity, and substandard drug compatibility. Furthermore, the surface coating or internal components of traditional rubber stoppers are easily corroded in strongly alkaline environments, potentially causing phenomena such as adhesion to the stopper wall, drug adsorption, and increased debris from punctures, affecting drug quality and safety.

[0004] While some acid and alkali resistant rubber stoppers exist, they generally suffer from insufficient resistance to strong alkalis, poor process adaptability, and difficulty in balancing crosslinking density and mechanical properties, failing to meet the sealing and compatibility requirements for long-term storage of strongly alkaline injectables. Therefore, developing a brominated butyl rubber stopper that is resistant to strong alkalis, has low dissolution, high stability, and excellent processability has become an urgent technical problem to be solved in the field of pharmaceutical rubber stoppers. Summary of the Invention

[0005] Based on the above background, this invention proposes a strong alkali-resistant brominated butyl rubber stopper. Using brominated butyl rubber as the rubber base material, a novel environmentally friendly carbon-nitrogen heterocyclic (triazine thiol) vulcanizing agent system is employed. A chemically stable styrene-ethylene / butene-styrene block copolymer (SEBS) is used as the organic filler in the rubber-plastic blend. Strong alkali-resistant hydroxyapatite and sodium aluminum silicate are added as inorganic fillers. Based on this main formulation, a strong alkali-resistant brominated butyl rubber stopper is prepared. The triazine thiol vulcanizing agent in the formulation is relatively stable and can crosslink with brominated butyl rubber. The reaction process does not produce nitrosamines, making it suitable for preparing chemically stable brominated butyl rubber with high drug compatibility. Adding SEBS as an organic filler during the mixing stage allows the small amount of residual double bonds in this material to co-crosslink with the brominated butyl rubber molecular chains during the triazine vulcanizing process, increasing the hardness of the vulcanized product. Simultaneously, this material is resistant to strong acids and alkalis, increasing the strong alkali resistance of the butyl rubber stopper. The inorganic fillers used in the formula are calcined kaolin, hydroxyapatite and sodium aluminum silicate. Sodium aluminum silicate is a strong base material and does not easily react with strong alkaline solutions. At the same time, this material is a good dispersant, which facilitates the uniform dispersion of various materials in the compound.

[0006] The raw materials for the alkali-resistant brominated butyl rubber stopper include: 90-95 parts brominated butyl rubber, 5-10 parts butyl rubber, 40-60 parts calcined kaolin, 10-15 parts hydroxyapatite, 15-25 parts sodium aluminum silicate, 1-3 parts titanium dioxide, 0.1-0.4 parts carbon black, 0.5-1.5 parts vulcanizing agent, and 10-20 parts organic filler.

[0007] In the formulation of strong alkali resistant brominated butyl rubber stoppers, brominated butyl rubber is used as the main material, and a small amount of butyl rubber is used as a color masterbatch to pre-disperse the colorant, reduce black and white spot impurities on the surface of the subsequent processed products, and ensure the color consistency of each butyl rubber stopper.

[0008] The vulcanizing agent is a triazine thiol vulcanizing agent, which is selected from 6-(diisopropylamino)-1,3,5-triazine-2,4-dithiol IPSH, 6-(dibutylamino)-1,3,5-triazine-2,4-dithiol BSH or 6-(aniline)-1,3,5-triazine-2,4-dithiol AF.

[0009] The brominated butyl rubber is grade 232 brominated butyl rubber from the Russian company OAO NIzhnekamskneftekhim; the sodium aluminum silicate is grade SIPERNAT 820A sodium aluminum silicate from Evonik.

[0010] The vulcanizing agent in the formulation is a carbon-nitrogen heterocyclic environmentally friendly vulcanizing agent, specifically a triazine thiol vulcanizing agent, such as IPSH. This triazine thiol vulcanizing agent (IPSH, etc.) has a three-carbon, three-nitrogen six-membered ring structure, which is relatively stable and can crosslink with brominated butyl rubber. Moreover, the reaction process does not produce nitrosamines and can be used to prepare chemically stable brominated butyl rubber with high drug compatibility.

[0011] The weight ratio of calcined kaolin to hydroxyapatite is 4-8:1.

[0012] The filler in the formula consists of four types: calcined kaolin, hydroxyapatite, sodium aluminum silicate, and organic filler.

[0013] Furthermore, the sodium aluminum silicate filler should have a suspension pH value (5% in water) in the range of 9.6-10.6 and a median diameter of 5.5-8.5 μm. Sodium aluminum silicate filler with strong base has good reinforcing effect and is not easy to react with strong base solution. At the same time, this material is a good dispersant, which facilitates the uniform dispersion of various materials in the compound.

[0014] Preferably, the organic filler is a styrene-ethylene / butene-styrene block copolymer (SEBS), wherein the styrene content is 27.5-30.5%. This material is added as an organic filler during the mixing process for rubber-plastic blending. The small amount of residual double bonds in SEBS can co-crosslink with the brominated butyl rubber molecular chains during the triazine vulcanizing process, significantly increasing the hardness of the vulcanized product. Simultaneously, SEBS is resistant to strong acids and alkalis, which can increase the alkali resistance of butyl rubber stoppers.

[0015] In the aforementioned formulation, hydroxyapatite is an inorganic mineral filler with the chemical formula Ca. 10 (PO4)6(OH)2 is chemically extremely stable, exhibiting no dissolution or acid-base reaction in strongly alkaline drug solutions, effectively avoiding the pH shift issue caused by the dissolution of conventional inorganic fillers under strong alkaline conditions. Furthermore, hydroxyapatite's needle-like / granular crystal structure complements the layered structure of calcined kaolin, forming a three-dimensional reinforcing network within the rubber substrate, enhancing the physical and mechanical properties (hardness, abrasion resistance, tear resistance) of the stopper. In addition, hydroxyapatite is a medical-grade biocompatible filler, non-toxic, and exhibits good compatibility with brominated butyl rubber, SEBS, and other substrates, without introducing additional leachates, further ensuring the drug compatibility of the stopper.

[0016] The brominated butyl rubber is grade 232 brominated butyl rubber from the Russian company OAO NIzhnekamskneftekhim; the sodium aluminum silicate is grade SIPERNAT 820A sodium aluminum silicate from Evonik; and the hydroxyapatite is medical-grade nano-hydroxyapatite with a particle size of 50-100 nm and a specific surface area of ​​30-50 m² / g. 2 / g.

[0017] The alkali-resistant brominated butyl rubber stopper further includes 0.5-2 parts stearic acid, 0.5-5 parts magnesium oxide, and 0.5-3 parts plasticizer, wherein the plasticizer is polyethylene glycol.

[0018] The strong alkali resistant brominated butyl rubber stopper comprises 95 parts brominated butyl rubber, 5 parts butyl rubber, 40 parts calcined kaolin, 10 parts hydroxyapatite, 20 parts sodium aluminum silicate, 2 parts titanium dioxide, 0.2 parts carbon black, 1.0 part vulcanizing agent, 10 parts organic filler styrene-ethylene / butene-styrene block copolymer SEBS, 1 part stearic acid, 3 parts magnesium oxide, and 2 parts plasticizer.

[0019] In view of the above formulation, the present invention also provides a method for preparing the strong alkali-resistant brominated butyl rubber stopper, the method comprising the following steps:

[0020] (1) Color masterbatch mixing: Butyl rubber, titanium dioxide and carbon black are mixed and then subjected to intensive mixing and open milling to uniformly disperse the colorant and obtain color masterbatch; (2) Mixing: The color masterbatch is mixed with brominated butyl rubber, calcined kaolin, hydroxyapatite, sodium aluminum silicate, vulcanizing agent, organic filler, stearic acid, magnesium oxide and plasticizer. After intensive mixing and open milling, the mixture is extruded and calendered to obtain a rubber sheet. (3) Vulcanization molding: The film is placed in a vulcanizing machine for vulcanization treatment; (4) Post-treatment: Remove the edges of the vulcanized rubber sheet, clean and dry it to obtain a strong alkali resistant brominated butyl rubber stopper.

[0021] In step (2), the mixing process is divided into four stages, specifically: (2.1) Add brominated butyl rubber, color masterbatch, half calcined kaolin, half hydroxyapatite, stearic acid, and plasticizer to the internal mixer, and press and mix for 240s, or stop when the temperature of the mixing chamber reaches 110℃. (2.2) Add the remaining calcined kaolin, remaining hydroxyapatite, sodium aluminum silicate, and organic filler into the internal mixer, sweep away the powder and continue mixing for 300s, or stop when the temperature of the mixing chamber reaches 125℃. (2.3) Add magnesium oxide to the internal mixer and continue mixing until the temperature of the mixing chamber reaches 130°C, then discharge the rubber to obtain the mixed rubber. (2.4) Place the intensive rubber in a two-roll mill, add the vulcanizing agent, roll and pour the rubber to mix evenly, cool the rubber, and then extrude and calender to obtain rubber sheets.

[0022] The vulcanization process parameters in step (3) are: vulcanization temperature 170-190℃, vulcanization pressure 15-20MPa, and vulcanization time 8-15min.

[0023] The present invention has the following beneficial effects: (1) The formulation uses a novel carbon-nitrogen heterocyclic environmentally friendly vulcanizing agent, specifically a triazine thiol vulcanizing agent (IPSH, etc.). This vulcanizing agent has a three-carbon, three-nitrogen six-membered ring structure, which is relatively stable and can be crosslinked with brominated butyl rubber. Moreover, the reaction process does not produce nitrosamines and can be used to prepare brominated butyl rubber with stable chemical properties and high drug compatibility.

[0024] (2) Add organic filler SEBS to the formula and add it in the middle stage of mixing for rubber-plastic blending. Some structures in SEBS may co-crosslink with brominated butyl rubber molecular chains during the vulcanization process of triazine vulcanizing agent, which significantly increases the hardness of the vulcanized product. At the same time, SEBS is resistant to strong acids and alkalis, which can increase the alkali resistance of butyl rubber stoppers.

[0025] (3) The inorganic filler part uses alkali-resistant inorganic materials such as sodium aluminum silicate and hydroxyapatite. These materials are alkaline fillers, have good reinforcing effect and are not easy to react with strong alkaline solutions. At the same time, they are good dispersants, which facilitate the uniform dispersion of various materials in the compound. Detailed Implementation

[0026] The present invention will be further described below with reference to specific embodiments.

[0027] The brominated butyl rubber uses halogenated butyl rubber as the rubber base material, preferably the 232 grade brominated butyl rubber from the Russian company OAONIzhnekamskneftekhim; the sodium aluminum silicate is preferably the HL-380SIPERNAT 820A grade sodium aluminum silicate from Evonik; the vulcanizing agent is preferably the IPSH grade triazine vulcanizing agent from Kawaguchi Chemical Industry Co., Ltd., with magnesium oxide as the acid scavenger; the organic filler is preferably the 6153 grade styrene-ethylene / butene-styrene block copolymer from TSRC Corporation; and the plasticizer is preferably the PEG4000 grade polyethylene glycol from Krohne Chemical Co., Ltd.

[0028] Example 1 A brominated butyl rubber stopper resistant to strong alkalis. (1) Preparation: Weigh each raw material according to the requirements of the formula table for later use. The formula tables are shown in Table 1-1 and Table 1-2.

[0029] The organic filler is a styrene-ethylene / butene-styrene block copolymer (SEBS), wherein the styrene content is 27.5%~30.5%.

[0030] (2) Color masterbatch mixing: Weigh appropriate amounts of raw materials according to the proportions of butyl rubber, titanium dioxide and carbon black in the formula, and carry out intensive mixing and open mixing to make the colorant evenly dispersed; (3) Mixing: Weigh the masterbatch compound and other raw materials except butyl rubber, titanium dioxide and carbon black according to the weight of the raw materials in the formula, and mix, open, and extrude and calender according to the following steps.

[0031] (3.1) Add brominated butyl rubber, color masterbatch compound, half calcined kaolin, half hydroxyapatite, stearic acid, and plasticizer to the internal mixer and press and mix for 240s or until the temperature of the mixing chamber reaches 110℃; (3.2) Add the remaining calcined kaolin, remaining hydroxyapatite, sodium aluminum silicate, and organic filler powder to the internal mixer and continue mixing for 300s or until the mixing temperature reaches 125℃; (3.3) Add magnesium oxide to the internal mixer and mix until 130℃ before discharging; (3.4) Add vulcanizing agent to the open mill, roll and pour the rubber, mix evenly, cool the rubber and extrude and calender it.

[0032] (4) Vulcanization molding: The extruded and calendered rubber sheet is placed in a vulcanizing machine for vulcanization; (5) Remove the edges and clean to obtain a strong alkali resistant brominated butyl rubber stopper.

[0033] The formulation composition is shown in Tables 1-1 and 1-2 below, and the preparation method is the same as in Example 1.

[0034] Table 1-1 shows the formulations for Examples 1-7.

[0035] Tables 1-2 are the formulation tables for Examples 8-10.

[0036] The performance of the rubber compounds prepared in Examples 1-10 was tested and analyzed. Their processing performance and flowability met normal production requirements, as shown in Table 2. According to the performance indicators of the rubber compounds in Examples 1-3, as the amount of sodium aluminum silicate increased, the MH and MH-ML values ​​and hardness decreased slightly. MH-ML can characterize the crosslinking density of the rubber. Because sodium aluminum silicate is a porous inorganic filler, it has an adsorption effect on small molecule vulcanizing agents, and its reinforcing effect in rubber is generally weak. With the increase of its dosage, due to its adsorption effect on vulcanizing agents, the vulcanization activity and hardness of the rubber compound decreased. Therefore, a dosage of 15-25 parts is appropriate, which can ensure good reinforcing effect and alkaline compatibility without affecting the vulcanization activity of the rubber compound. As can be seen from the compound performance data of Examples 2 and 4-7, with the increase of the amount of organic filler (SEBS), the MH-ML value of the compound first increases and then decreases. Simultaneously, compared with the compound without SEBS, the hardness of the compound is significantly increased. This is because certain structures of SEBS undergo co-crosslinking with brominated butyl rubber segments during the vulcanization process of the triazine thiol vulcanizing agent (IPSH) vulcanizing system. However, with the increase of the amount of organic filler (SEBS), the MH-ML value of the compound slightly decreases. Since the MH-ML value is positively correlated with the degree of crosslinking of rubber, when the organic filler SEBS is added in excess, it has a slight effect on the crosslinking density of the compound, especially after increasing to 25 parts. Therefore, the amount of organic filler (SEBS) should be between 10-20 parts. Based on Examples 6 and 8-10, with a fixed weight percentage of kaolin, the performance of the rubber compounds with different kaolin and hydroxyapatite ratios was compared. The data in the table shows that the hardness of the rubber compound gradually increases with the increase of the hydroxyapatite ratio, indicating a significant improvement in the physical properties of the rubber under the synergistic reinforcement of kaolin and hydroxyapatite. Appropriately increasing the hardness can improve the machine speed and smoothness of butyl rubber stoppers. However, due to the special use of butyl rubber stoppers, excessively high hardness, such as 57 or higher, can cause puncture and chipping problems during compounding. Furthermore, nano-grade hydroxyapatite is expensive. Therefore, considering the special use and cost of the rubber stoppers, a kaolin to hydroxyapatite ratio of 4-8:1 is most suitable.

[0037] Table 2 Properties of the compound rubber (Test conditions: 185℃×5min)

[0038] Ten samples each of the strong alkali-resistant brominated butyl rubber stopper products prepared using Examples 1, 2, 3, 4, 5, and 6 above, and the conventional sulfur magnesium oxide system stopper products were placed in stoppered conical flasks. 100 ml of pH 12.0 phosphate buffer solution was added to submerge the stoppers. Accelerated testing was conducted in a constant temperature incubator at 60℃±1℃ and 75%±5% relative humidity. After 7 days, the pH value of the phosphate buffer solution was measured, and a blank control solution was used for calibration. The absorbance in the wavelength range of 220nm-360nm was measured according to the UV-Vis spectrophotometry method (Volume IV, 0401) of the 2025 edition of the Pharmacopoeia of the People's Republic of China. The results are as follows: Table 3. Accelerated pH test results

[0039] Table 4. Results of accelerated UV absorbance test

[0040] Based on the above experimental data, compared with ordinary butyl rubber stoppers, the brominated butyl rubber stopper of the present invention exhibits a smaller pH change in the solution during accelerated testing; simultaneously, the UV absorbance value measured using a blank control as a calibration measure is also significantly lower. The smaller pH change indicates that the stopper did not react with the solution during the accelerated testing; while absorbance primarily detects the content of organic compounds such as benzene rings and conjugated double bonds in the solution. A lower absorbance value indicates less leaching of the stopper into the solution and better compatibility. Therefore, the brominated butyl rubber stopper of the present invention possesses superior resistance to strong alkalis and is less likely to react with strong alkaline solutions. Furthermore, the accelerated testing results for pH and absorbance show that the brominated butyl rubber stopper produced using triazine thiol vulcanizing agent (IPSH) as the main vulcanizing agent exhibits significantly better resistance to strong alkalis than traditional sulfur vulcanized rubber stoppers. In addition, the resistance to strong alkalis also slightly improves with increasing amounts of sodium aluminum silicate and the organic filler SEBS.

[0041] Example 11 Based on Example 2, the styrene content in the organic filler SEBS was changed, and samples were prepared and tested.

[0042] Example 2: The organic filler SEBS has a styrene content of 27.5%-30.5%.

[0043] Example 11: The organic filler SEBS has a styrene content of 11.5%-14.5%.

[0044] Example 12: The organic filler SEBS has a styrene content of 16.5%-19.5%.

[0045] Example 13: The organic filler SEBS has a styrene content of 31.5%-34.5%.

[0046] Table 5. Properties of the compound rubber (Test conditions: 185℃×5min)

[0047] Table 6. Accelerated pH Test Results

[0048] Table 7 Results of accelerated UV absorbance test

[0049] As shown in the compound performance table above, the MH-ML value of the compound increases with the increase of styrene block content in SEBS. This indicates that excessive styrene content in SEBS will affect the degree of crosslinking of the compound. This is because styrene blocks have a rigid structure, and as their content increases, they increase the hindrance to the molecular chains of the compound, thus affecting the vulcanization and crosslinking process. However, the hardness of the compound increases with the increase of styrene content in SEBS. In addition, different styrene contents of SEBS have little effect on the resistance of the rubber stopper to strong alkalis. Therefore, considering both the hardness and the degree of crosslinking of the product, SEBS with a styrene content of 27.5%-30.5% is the most suitable.

[0050] The above embodiments are merely preferred technical solutions of the present invention and should not be considered as limitations on the present invention. The embodiments and features described in these embodiments can be arbitrarily combined without conflict. The scope of protection of the present invention should be limited to the technical solutions described in the claims, including equivalent substitutions of the technical features described in the claims. That is, equivalent substitutions and improvements within this scope are also within the scope of protection of the present invention.

Claims

1. A alkali-resistant brominated butyl rubber stopper, characterized in that, The raw materials for the alkali-resistant brominated butyl rubber stopper include: 90-95 parts brominated butyl rubber, 5-10 parts butyl rubber, 40-60 parts calcined kaolin, 10-15 parts hydroxyapatite, 15-25 parts sodium aluminum silicate, 1-3 parts titanium dioxide, 0.1-0.4 parts carbon black, 0.5-1.5 parts vulcanizing agent, and 10-20 parts organic filler; the vulcanizing agent is a triazine mercaptan vulcanizing agent, selected from 6-(diisopropylamino)-1, The organic filler is 3,5-triazine-2,4-dithiol IPSH, 6-(dibutylamino)-1,3,5-triazine-2,4-dithiol BSH, or 6-(aniline)-1,3,5-triazine-2,4-dithiol AF; the organic filler is styrene-ethylene / butene-styrene block copolymer SEBS, and the styrene content should be 27.5% to 30.5%; the hydroxyapatite has a particle size of 50-100 nm and a specific surface area of ​​30-50 m². 2 / g, wherein the sodium aluminum silicate is an alkaline inorganic filler, stable in strong alkalis, with a median diameter of 5.5-8.5μm and a pH value of 9.6-10.

6.

2. The strong alkali-resistant brominated butyl rubber stopper according to claim 1, characterized in that, The weight ratio of calcined kaolin to hydroxyapatite is 4-8:

1.

3. The strong alkali-resistant brominated butyl rubber stopper according to claim 1, characterized in that, The alkali-resistant brominated butyl rubber stopper also includes 0.5-2 parts stearic acid, 0.5-5 parts magnesium oxide, and 0.5-3 parts plasticizer.

4. The strong alkali-resistant brominated butyl rubber stopper according to claim 3, characterized in that, The plasticizer is polyethylene glycol.

5. A strong alkali-resistant brominated butyl rubber stopper according to any one of claims 1-4, characterized in that, The strong alkali resistant brominated butyl rubber stopper comprises 95 parts brominated butyl rubber, 5 parts butyl rubber, 40 parts calcined kaolin, 10 parts hydroxyapatite, 20 parts sodium aluminum silicate, 2 parts titanium dioxide, 0.2 parts carbon black, 1.0 part vulcanizing agent, 10 parts organic filler styrene-ethylene / butene-styrene block copolymer SEBS, 1 part stearic acid, 3 parts magnesium oxide, and 2 parts plasticizer.

6. The method for preparing a strong alkali-resistant brominated butyl rubber stopper according to any one of claims 1-5, characterized in that, The method includes the following steps: (1) Color masterbatch mixing: Butyl rubber, titanium dioxide and carbon black are mixed and then subjected to intensive mixing and open milling to uniformly disperse the colorant and obtain color masterbatch; (2) Mixing: Mixing is divided into 4 stages, specifically: (2.1) Add brominated butyl rubber, color masterbatch, half calcined kaolin, half hydroxyapatite, stearic acid, and plasticizer to the internal mixer, and press and mix for 240s, or stop when the temperature of the mixing chamber reaches 110℃. (2.2) Add the remaining calcined kaolin, remaining hydroxyapatite, sodium aluminum silicate, and organic filler into the internal mixer, sweep away the powder and continue mixing for 300s, or stop when the temperature of the mixing chamber reaches 125℃. (2.3) Add magnesium oxide to the internal mixer and continue mixing until the temperature of the mixing chamber reaches 130°C, then discharge the rubber to obtain the mixed rubber. (2.4) Place the intensively mixed rubber in a two-roll mill, add the vulcanizing agent, roll and pour the rubber to mix evenly, cool the rubber, and then extrude and calender it to obtain rubber sheets. (3) Vulcanization molding: The film is placed in a vulcanizing machine for vulcanization treatment; (4) Post-treatment: Remove the edges of the vulcanized rubber sheet, clean and dry it to obtain a strong alkali resistant brominated butyl rubber stopper.

7. The preparation method according to claim 6, characterized in that, The vulcanization process parameters in step (3) are: vulcanization temperature 170-190℃, vulcanization pressure 15-20MPa, and vulcanization time 8-15min.

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