Overview of Safety Characteristics of Film-coated Rubber Plug Film

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Overview of Safety Characteristics of Film-coated Rubber Plug Films
Time:2014-11-25 15:55:24  from:China Pharmaceutical Packaging Association

[China] Nearly 10 years after the elimination of natural rubber plugs in 2005, the pharmaceutical rubber plug industry in China has made considerable progress and made due contributions to the pharmaceutical industry. The variety of medicinal rubber stoppers has also changed greatly, from the original halogenated butyl rubber stoppers to the present film-covered rubber stoppers. Although Chinese medicinal rubber plugs, especially film-covered rubber plugs, have made great progress in recent years, they still face some practical difficulties in actual production, declaration and use. In order to satisfy the safety of rubber plugs and film-covered materials, and make the varieties of film-covered rubber plugs develop healthily, so as to meet the actual needs of the domestic drug market, the application of film-covered rubber plugs and the safety characteristics of film materials are summarized.

I. The Concept of Film-covered Rubber Plug

Film-covered rubber stoppers refer to the products of rubber stoppers, such as fluorine-coated rubber stoppers, which have a strong layer, such as ldquo, film-coated rubber stoppers, on the contact surface between rubber stoppers (bare stoppers) and drugs. The rubber plug formed by dipping and spraying technology can be called film-coated rubber plug, such as film-coated rubber plug formed by polydimethylsiloxane film.

When using ordinary rubber stoppers, the compatibility problems may occur because of the interaction between rubber stoppers and sensitive drugs because of the direct contact between rubber stoppers and sensitive drugs. By adding a barrier plastic film on the surface of the rubber plug, the rubber plug can shield the contact between the rubber plug and the drug, which can effectively reduce the absorption, adsorption, leaching and penetration between the rubber plug and the drug, thereby effectively reducing or delaying the occurrence and development of compatibility problems and improving the long-term stability of the drug.

II. Production and Application of Film-coated Rubber Plug at Home and Abroad

Overseas, Japan began to produce butyl rubber bottle stoppers in 1957, and developed countries in Europe and America also realized mass production of medicinal butyl rubber bottle stoppers in early 1970. In China, the mass production of medicinal butyl rubber bottle stoppers was not started until 1992. At the same time, the covering technology of butyl rubber stopper has been developed earlier abroad, and the technology is relatively mature. For example, American Seattle Company, Japan Daxie Nitro Company, Belgium Helvoet Company, etc., all have different specifications of the covering butyl rubber stopper, and all have the capacity of mass production. As early as the 1980s, Daikyo Seiko first developed the film-covered rubber plug and applied for a patent. At present, some domestic butyl rubber plug manufacturers’technicians through a large number of experiments, constantly explore and exchange, can also produce a relatively stable quality of film-covered butyl rubber plug in batches. Among the 35 kinds of film-covered rubber plugs approved by the State Bureau, 18 of them adopt fluorine-containing film material, which is the main form of film material used for film-covered rubber plugs in China at present. From the number of varieties approved in previous years, the approval of fluorine-containing film-covered rubber plugs is relatively stable, the number of approved in each year is shown in Table 1.

Because of the excellent chemical properties of the film-covered rubber plug, it has been widely used in many sensitive drugs, such as antibiotics and biochemical agents at home and abroad. In view of the wide application of film-covered rubber plugs, the chapter of medicinal rubber seals has been rewritten in the new edition of American Pharmacopoeia. It is specially stipulated that even if the plug with barrier film (such as fluorine film) is used, the part of the plug must meet the relevant requirements of the medicinal plug, mainly in order to control the quality of the plug itself. Therefore, the coating process is only a process of further optimizing the quality of qualified medicinal plugs to meet the higher requirements of sensitive drugs, rather than covering up the non-conformity of low-quality plugs. This also reflects the international recognition of plug film covering technology and fluorine film material, although at the same time, no fluorine film material for plug is applied for DMF and activated.

Ⅲ、Common Fluorine Film Materials and Suppliers

& ldquo; Teflon & rdquo; (transliteration of Teflon) is often used to address fluorinated resins and their products, but in fact & ldquo; Teflon & rdquo; is a registered trademark used by DuPont Company on a series of fluorinated polymer products. DuPont Co initially used “ Teflon” as the trademark of teflon resin, and later developed products including Teflon AF (amorphous fluoropolymer), Teflon FEP (perfluoroethylene propylene resin), Teflon FFR (fluoropolymer foam resin), Teflon NXT (fluoropolymer resin), Teflon PFA (perfluoroalkoxy resin) and other products, and for the ethylene (ethylene four) Fluoroethylene copolymer, its registered trademark is & ldquo; Tefzel & rdquo;.

International manufacturers of fluoroplastics mainly include DuPont, Klein, Ciba Refining, 3M, Acoma, Dajin, Asahi Nitrogen, Solvey and so on, while suppliers of fluoroplastics for rubber plug film mainly include DuPont, Saint-Gobain and Asahi Nitrogen.

Ⅳ、Properties of Fluorine Film Material
Structure and Chemical Stability of Fluorine Films
The fluoroplastics film used for covering rubber plug contains tetrafluoroethylene polymer. Teflon is the product of replacing hydrogen atom in ethylene with fluorine atom. The monomer structure is shown in Fig. 1.

There are high bond energy carbon-fluorine bonds in its molecular structure. The substitution of fluorine atoms makes its molecule form a helical configuration. Fluorine atoms form a cylindrical shell, as shown in Figure 2.

Inert spiral perfluorinated shell makes fluoroplastics have a series of outstanding properties. It has excellent chemical stability and biological inertia. It can resist strong acid, alkali and various organic solvents, heat resistance, dielectric property, self-lubrication and aging resistance. Even at high temperature, aqua regia has no effect on it. See Table 2. At the same time, fluorine materials have very low surface free energy, only 0.019N/m, which is the smallest surface free energy among known solid materials, so almost all solid materials can not adhere to its surface, which is also one of the main reasons why it is widely used in food and drug production pipelines and containers.

The fluoroplastic film used for the film-covered rubber plug is not only stable to other substances and environment, but also does not use any processing aids in the film-forming process. Its fluorine-containing resin composition is 100%.

Heat Resistance of Fluorine Film Material

Fluorine material is a high temperature resistant polymer material. Because the main chain of fluorine material is saturated C-C bond, the branch chain is saturated C-F bond with high bond energy, and the large functional group-F has shielding effect, the fluorine material shows high temperature resistance. For example, the long-term service temperature of FEP (perfluoroethylene propylene) is an important index to measure the stability of materials. The long-term service temperature of ETFE (ethylene-tetrafluoroethylene) is 165 (?) at 205 (?) C. Therefore, the sterilization temperature of the rubber plug will not have any effect on the fluorine film rubber plug, but the effect of extreme temperature should be considered in the experiment because of the high vulcanization temperature of the rubber plug.

According to the data provided by DuPont Company, the weight loss of ETFE membranes occurs only at 260 C, i.e. at temperatures greater than 260 C, the escape products are analyzed as tetrafluoroethylene and trifluoromethane. FEP film began to lose weight at about 400 C, and constant weight at 121 – 300 C. No precipitates were found. The sterilization temperature of film-covered rubber stoppers used in pharmaceutical factories is generally 121 C, and the vulcanization temperature of film-covered rubber stoppers is generally 150-160 C, which indicates that there will be no weight loss in the production and use of film-covered rubber stoppers.

Ⅴ conclusion
In summary, the conclusions are as follows: (1) Fluoroplastics film used for film-covered rubber plug has high bond energy carbon-fluorine bond, fluorine atom substitution makes its molecule form a helical configuration, fluorine atom forms a cylindrical shell. Therefore, the film material of the film-covered rubber plug has strong stability, excellent chemical stability, heat resistance, dielectric property, self-lubrication and aging resistance, and is insoluble or swelled in any known solvent. (2) Film forming process does not require fillers, antioxidants, vulcanizates and other additives as rubber products, nor vulcanization reaction process, and its fluororesin composition is 100%. (3) The FEP film began to lose weight at about 400 C, and remained constant in the range of 121-300 C. No precipitates were found. The sterilization temperature of film-covered rubber stoppers used in pharmaceutical factories is generally 121 C, and the vulcanization temperature of film-covered rubber stoppers is generally 150-160 C. It shows that no weightlessness will occur in the production and use of film-covered rubber plugs. (4) The long-term service temperature of FEP (perfluoroethylene propylene) and ETFE (ethylene-tetrafluoroethylene) is 205 C and 165 C respectively. Therefore, the sterilization temperature of the rubber plug will not have any effect on the fluoroethylene rubber plug.

Review of safety concerns of fluoroplastics

Safety concerns caused by Teflon materials mainly focus on ammonium perfluorooctanate, an additive used in fluoroplastic resins. Perfluorooctanoic acid and its salts (i.e. perfluorooctanoic acid, PFOA) are one of the most difficult-to-degrade organic pollutants known. They have high bioaccumulation and multiple toxicities, which not only cause human respiratory problems, but also may lead to neonatal death. Global pollution has attracted much attention. In December 2002, the 34th Joint Meeting of Chemical Committees convened by OECD defined it as a substance that persists in the environment, has biological savings and is harmful to human beings.

PFOA is banned under the US Toxic Substances Control Act (US TSCA) because it can remain in humans for as little as four years and up to half a lifetime. DuPont has never reported that ammonium perfluorooctanate (C-8), a key raw material for manufacturing Teflon, may pose potential health hazards. Therefore, DuPont was accused by the US Environmental Protection Agency of violating the toxic substance reporting clause in 2004. The United States Environmental Protection Agency (EPA) launched the 2010-2015 PFOA Environment Program. Eight companies involved in the program, Dupont, Klein, Ciba Refining, 3M, Acoma, Dajin, Asahi and Solvey, agreed to reduce the emissions of perfluorooctanoic acid (PFOA) as well as its long-chain homologues and any other compounds that may decompose into PFOA. At the same time, it will further reduce the content of the above substances in the products.

Referring to the decision of the United States, the European Union issued the resolution of 2004/1935/EC directive on materials and substances in contact with food, and PFOA was also banned. On 27 December 2006, the European Parliament and the Council of Ministers jointly issued the Directive on Restricting the Sale and Use of Perfluorooctane Sulfonic Acid (PFOS), which limits the use and marketing of PFOS products. PFOS is not allowed to be sold as a constituent substance or element with a concentration or mass equal to or exceeding 0.005%. Restrict the use of PFOS in finished and semi-finished products. Products, semi-finished products and parts containing PFOS concentration or mass equal to or exceeding 0.1% (1000ppm) shall not be sold. The limitations include all products intentionally adding PFOS, including coated surfaces for specific parts and products, where textiles and coated materials are limited to 1μ g/m2.