Influence of the extractability of the hottest ela

2022-09-23
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The influence of the extractability of elastomers on the closure and sealing of drug bottles

elastomers have been used in pharmaceutical packaging for a long time to preserve drugs and drugs. In the early days, natural rubber was an ideal material. Up to now, it still occupies a dominant position in developing countries. Due to its high impurity content, high permeability, uneven quality, and latex allergy, the drug bottle stopper and seal made of natural rubber are only a physical barrier. Nowadays, natural rubber is no longer used in drug packaging in most countries, but replaced by synthetic rubber

elastomers that meet the current requirements of pharmaceutical packaging must have the following characteristics, including low content of additives and impurities, high impermeability to water and air, good chemical and biological inertia, aging resistance and heat resistance (sterilization), and easy to use a small amount of "clean" vulcanizing agent to achieve vulcanization. Only a few elastomers can meet all the above requirements

among all commercial elastomers, halogenated butyl rubber (chlorinated butyl rubber and brominated butyl rubber) has achieved great success in the application of drug packaging, realizing the loading and unloading work of samples, and is the first choice for drug bottle stopper and sealing applications all over the world. Halogenated butyl rubber polymer has high impermeability to water and gas, which is very important for the preservation of drugs. These polymers are highly saturated, so they have good oxidation resistance, heat resistance (sterilization) and aging resistance. They are chemically inert and nonpolar, so they will not lead to the absorption of drugs or water. Compared with ordinary butyl rubber, halogenated butyl rubber can be vulcanized effectively by using a small amount of "clean" vulcanizing agent. The bottle stopper made of halogenated butyl rubber also shows sufficient air tightness, sufficient rupture and tear strength and other physical properties

the trend of constantly seeking cleaning

see Figure 1 for the development trend of elastomers used for drug bottle closures in history

before 1940, natural rubber was mainly used for drug bottle stoppers until the emergence of butyl rubber. Due to its excellent barrier property and heat resistance and oxidation resistance, butyl rubber has been used in the manufacture of pharmaceutical corks since it was put on the market in the 1940s. Since the 1960s, halogenated butyl rubber, first chlorinated butyl rubber and then brominated butyl rubber, has gradually replaced other ordinary butyl rubber and been used in pharmaceutical/biomedical rubber plug applications. Today, halogenated butyl rubber is used in more than 90% of antibiotic seals, infusion seals and biomedical seals made in Europe, the United States and China. Compared with ordinary butyl rubber, halogenated butyl rubber has another advantage that it can be vulcanized with low content of clean vulcanizing agent, including sulfur-free and zinc free types. With the development of the industry, polytetrafluoroethylene and other coated corks have been continuously developed to meet the requirements. These corks are very expensive and have excellent sealing performance. Brominated isobutene p-methylstyrene copolymer elastomer (BIMM) is a very clean material, which can be vulcanized efficiently with a small amount of clean vulcanizing agent, and is a good substitute for expensive coated bottle closures (for sensitive drugs) and other needs

effect of extractability on drug quality/compatibility

halogenated butyl rubber extracts that can affect drug quality or compatibility are mainly oligomers, halogenated oligomers and other residual additives/by-products in polymers. The latter include dibutyl hydroxytoluene (BHT) and 1,3,5 trimethyl-2,4,6-phosphate tris (3,5 Di tert butyl-4-hydroxyphenyl) benzene (Irganox 1010) antioxidants, calcium stearate suspension and even some users complain that the instrument has problems with epoxy soybean oil (ESBO). Oligomers and halogenated oligomers are by-products of polymerization. These ring molecules, mainly C13 and C21 atomic groups, are generated based on the anti biting mechanism, involving isoprene monomers, as shown in Figure 2. Some of these formed oligomers can be halogenated in the manufacturing process

the residue and additive levels in halogenated butyl rubber and BIMM elastomer can be measured by gas chromatography (GC), as shown in Table 1. It can be seen that these residues and additives exist in large quantities in the cork manufacturing process and remain in the cork all the time. At the same time, it can be seen that BIMM elastomer has the highest purity and does not contain antioxidants, oligomers and ESBO

Table 2 shows the effectiveness of bottle stopper extracts including drug turbidity. In these tests, the antibiotic was placed in a single volatile atom group (18 hours) and its drug turbidity was measured. This is essentially to measure the effect of volatile monomers on the surface of drug powder to form a coating and prevent the drug itself from dissolving in water. We found that the surface area of drug powder plays an important role (because the surface area is more sensitive to volatile atomic groups in the formation of drug turbidity). The test also showed that only polar volatiles, including oligomers and BHT, had a great impact on the turbidity of the drug

super clean elastomer for drug packaging

bimm, also known as exxpro special elastomer, is the fourth generation of polyisobutylene based polymer, which was launched by ExxonMobil Chemical Company in the early 1990s. It is the cleanest elastomer used in pharmaceutical packaging today. The polymer has a completely saturated skeleton and has very good heat resistance, oxidation resistance and aging resistance. It also contains no oligomers, antioxidants and epoxidized soybean oil. BIMM can be effectively vulcanized by benzyl bromide, and the effective vulcanization can be achieved by using a lower content of vulcanizing agent. The structure of BIMM elastomer is shown in Figure 3

Figure 4 is the schematic diagram of the formation mechanism of drug turbidity. During storage, volatile atomic groups will migrate from the bottle stopper to the powder of the drug. Some of them will eventually be adsorbed to the surface of the drug powder and prevent the drug powder from dissolving in water. A large number of highly volatile atomic groups will lead to more water-insoluble drug powders and higher drug turbidity. Through transmission electron microscopy (TEM), we can find the water-insoluble drug powder in the recombinant solution. The diameter of particles ranges from tens to hundreds of nanometers

drug turbidity can be quantitatively measured by light scattering technology. The amount of insoluble drug powder in the reconstituted solution is directly related to the intensity of scattered light, which is expressed in scattered turbidity unit (NTU). Today, the turbidity detection accuracy of an advanced turbidimeter can reach 0.01ntu

drug turbidity research has been carried out in various commercial corks vulcanized with similar vulcanizing agents produced in the same process. In these studies, 100 mg of antibiotic drug powder obtained directly from drug manufacturers was put into thoroughly cleaned glass vials equipped with a 20 mm diameter cork. Turn the bottle upside down several times (make the drug powder fully contact the bottle stopper), and place it in the oven with the temperature set at 40 ℃. After storage for different times (up to 12 months), inject 3ml of ultra pure water into each bottle to recombine with the drug powder in the bottle, and then measure the turbidity of the solution with a turbidimeter

Figure 5 shows that the bottle stopper made of BIMM has extraordinary low resistance turbidity. This is because BIMM contains the least additive residues and by-products. Impact testing machines are divided into manual pendulum impact testing machine, semi-automatic impact testing machine, digital display impact testing machine, microcomputer controlled impact testing machine, drop hammer impact testing machine and non-metallic impact testing machine. Bottle plugs made of bromobutyl rubber with low BHT content are also better than bromobutyl rubber with high BHT oxidation dose

in the second study, the effect of different types of elastic bottle closures on drug turbidity was discussed. The drug used in the study is vancomycin, which comes directly from the drug manufacturer. As can be seen from Figure 6, the commercial butyl rubber bottle stopper has the highest turbidity, followed by the natural rubber bottle stopper. The high turbidity of butyl rubber bottle stopper is caused by the type and content of vulcanizing agent used. The brominated butyl rubber bottle stopper greatly reduces the turbidity of the drug. As expected, brominated butyl rubber coated bottle closures have very low drug turbidity because the coating acts as a barrier to minimize the migration of chemicals. Aiming at this special antibiotic, the bottle stopper made of BIMM was compared with the brominated butyl rubber coated bottle stopper in terms of drug turbidity

evaluation of cork extract

in order to reveal the effectiveness of BIMM and BIMM coated corks in reducing the amount of precipitates, we conducted a study to evaluate and compare the solution extractability of different commercial corks. High performance gas chromatography (HPLC) and gas chromatography mass spectrometry (GC-MS) were used in the study. In order to complete the test, it is necessary to thoroughly clean the glass vials and rubber plugs with different specifications of 2 mm, and fill them with 10 ml of high-purity ethanol. Then turn the bottle up and down several times, let the solvent fully contact the cork, and store it at room temperature for 3 months. Any nonvolatile extract in ethanol was analyzed by high performance liquid chromatography, while the volatile extract was analyzed by GC-MS. Isopropanol was also used for testing, and similar results were obtained. In this case, at the boiling point temperature of isopropanol (100 ml), within 1 hour, 20 grams of bottle stopper or 10 grams of reflux polymer

Figure 7 shows the HPLC chromatograms of extracts in isopropanol (IPA) of three different rubbers used in bottle stopper manufacturing. It can be clearly seen that BIMM has the least extract

figure 8 compares the levels of extracts in ethanol of various commercial BIMM bottle closures from different manufacturers. The HPLC peak areas of the extract under the same blocking time are listed in Table 3 and figure 8

it can be seen that in addition to stearic acid (1.84 minutes of blocking time), other nonvolatile extracts are suitable vulcanizing agents and additives for bottle stopper manufacturing. The results also showed that BIMM coated corks reduced but could not eliminate nonvolatile extracts

Figure 9 and table 4 compare the levels of ethanol extracts from various commercial bromobutyl rubber corks produced by different manufacturers. The scanning electron micrograph of tetrafluoroethylene coated brominated butyl rubber bottle stopper and polyvinylidene fluoride coated BIMM bottle stopper is shown in Figure 10. The properties of the coating and elastomer have been confirmed by Fourier transform infrared spectroscopy (FTIR). We can observe in Table 4 that except BHT (2.12 min block time) and stearic acid (1.83 min block time), all other nonvolatile extracts may come from other vulcanizing agents and additives used in bottle stopper manufacturing. At the same time, it shows that the non-volatile extractability of brominated butyl rubber bottle stopper is higher than that of BIMM bottle stopper (pay attention to the difference between the relative concentration scales in Fig. 8 and Fig. 9). In addition, although the brominated butyl rubber coated bottle stopper has low extractability, new precipitates (a, B, c) do not appear on the uncoated rubber stopper

in order to identify and quantify the volatile extracts of bottle closures, we used gas chromatography-mass spectrometry (GC-MS) technology. This technology can identify and detect low volatile extracts at the level of 1 ppm. The volatile extracts of BIMM stoppers and coated b1msm bottle stoppers are shown in Table 5. GC-MS is shown in Figure 11

data

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