There are three vulcanisation methods: with sulfur, with bifunctional reagents and with peroxides. Most importantly, the vulcanisation method determines which contaminations will be present in the product. The vulcanisation density is the number of bonds between different chains per volume-unit.

Silicates, silicic acid, calcium carbonate or barium sulfate are used as fillers. Silicates and silicic acid make rubber more sustainable. Colourings for rubber are for example titanium dioxide and iron oxides. It is better to avoid organic colourings due to the chance of migration of the colouring to the rubber surface, followed by migration into the preparation.

The oldest form of rubber is natural rubber. The basic elastomer of natural rubber is taken from the latex of the rubber tree (Hevea brasiliensis, Euphorbiacea family). Latex consists of carbohydrates, water, fatty acids, proteins and stearines. The complex composition of latex varies significantly with origin, season, etc. This variation in composition is the main disadvantage when using this material in pharmaceutical products.

Natural rubber consists of polyterpenes. The gross formula of this basic elastomer in natural rubber is (C₅H₈)n. The module is isoprene (the base of all terpenoides). It is a polyunsaturated polymer with a structure as shown in Fig. 24.1. The value of n is very high; the molecular weight lies between 200.000 and 300.000.

The chemical structure of the natural latex product determines the characteristics of the rubber produced from that latex:

The basic elastomer of butyl rubber is the synthetized polymer poly-isobutylene with approximately 3 mol% isoprene. In case of the halogen butyl rubbers the isoprene is replaced by halogen isoprene. The structure of the basic elastomer is shown in Fig. 24.1. The basic elastomer of butyl rubber contains relatively few unsaturated bonds compared to the basic elastomer of natural rubber. The reactivity of butyl rubber is therefore less than that of natural rubber. To advance the vulcanization process, a higher concentration of reagents and/or a longer reaction time and a higher reaction temperature are therefore necessary. This relatively high amount of additives in butyl rubber can cause problems when it comes into contact with the pharmaceutical preparations. ‘Leaching’ may occur, where dispersed (not chemically bound) additives migrate to the surface of the rubber, followed by extraction into the preparation.

When producing the bromo- and chlorobutyl rubbers, the halogen basic elastomer is used. Like the non-halogen basic elastomer, this contains relatively few unsaturated bonds. The halogen atom activates the double bond and increases the reactivity of the basic elastomer. Therefore no extra measures to accelerate the vulcanization process have to be taken, unlike the production of butylrubber. The halogen butylrubbers therefore have largely replaced butylrubber.

The chemical structure of the halogen basic elastomer determines the characteristics of the halogen rubber which is synthesised from this basic elastomer:

Summarising: the mechanical characteristics of halogen butyl rubbers are not optimal (stronger deformation, less elastic than natural rubber), but the saturated structure leads to excellent chemical characteristics (see Table 24.5).

Rubber stoppers to close injection- or infusion bottles and –bags can be coated with a thin layer of a polymer that resembles Teflon (Teflon = polytetrafluorethene, PTFE). The result is a chemically inert stopper with significantly less “leaching” of substances from the rubber.

The basic elastomer for silicone rubber is a linear polysiloxane, built from dimethyl siloxane units with a small amount methylvinyl siloxane groups. The ends of the chains are formed from trimethyl siloxane- or dimethylvinyl siloxane groups. The structure of the basic elastomer is shown in Fig. 24.1. Peroxides are usually used for the crosslinking of silicone rubbers (for example dicumyl peroxide or 2,4-dichlorobenzoyl peroxide).

To improve tear resistance, the additive silicic acid can be added. Other additives are usually not necessary, so migration of substances from the final product into the pharmaceutical preparation will usually be limited to residues of the peroxide. By the right choice of the peroxide and adequate after treatment of the final product this problem can be reduced. The Ph. Eur. contains a test for the presence of peroxide residues in the elastomer.

Silicone rubber, like other rubbers that are produced following the peroxide method, can give an aldehyde odour shortly after production. This is caused by traces of peroxide breakdown products. The odour disappears with time or after steam sterilisation.

Silicone rubber is very resistant to ageing and oxidation. It shows a very high permeability to gas and water vapour, which significantly reduces the pharmaceutical usefulness. Silicone rubber is very resistant to a wide range of chemicals. It is resistant to weak acids and alkali, salt solutions and mono- or multivalent alcohols and phenols. However, it is not resistant to strong acids and bases. In low molecular solvents (ketones, esters, aliphatic, aromatic and chlorinated hydrocarbons) a reversible swelling of the elastomer occurs. Many preservatives and active substances are strongly adsorbed into silicone rubber.

The mechanical characteristics of silicone rubber are very highly independent of temperature. The elastomer keeps its original hardness and elasticity with temperatures lower than -50 °C. Resistance to high temperatures is also very good (to 250 °C). Addition of metal oxides to silicone rubber can improve the temperature resistance even further.

The basic elastomer ethylene propylene monomer (EPM) is generated by copolymerisation of ethylene and propylene. As the polymer chain does not have double bonds, vulcanisation takes place with the use of organic peroxides. The ethylene propylene rubber that is thus generated contains no double bonds. Therefore, the product is inert and has a long shelf life.

Ethylene propylene diene polymers (EPDM) are basic elastomers with double bonds in the side chain. They are generated by adding small amounts of diene monomers in the copolymerisation of ethylene and propylene. Due to the presence of this unsaturated bond in the basic elastomer both vulcanisation with peroxides and vulcanisation with sulfur are possible. Vulcanisation with peroxides is usually chosen. This generates a product that is relatively inert and well resistant to ageing.

When synthesising ethylene propylene rubber usually a filler (for example aluminium silicate or calcium carbonate) and a plasticiser (for example an aromatic hydrocarbon) are added and a colouring if necessary.

As with silicone rubber, ethylene propylene rubber can give an aldehyde odour. Ethylene propylene rubber is highly resistant to water, alkali and dilute acids, and moderately to poorly resistant to hydrocarbons, lipids and concentrated acids. It is resistant to the high temperatures of steam sterilisation.

The container closure system seals the primary container after filling, protecting the contents from interactions with the external environment. In the majority of cases, the closure also allows access and use of the product. Where tamper evidence is required the closure system must be able to show that the container has been opened.

In order to provide these functions, the forms and methods used to provide an effective seal vary widely. The closure systems used in pharmacy usually depend on a system were a relatively soft material is pressed onto a hard material. The softer, more resilient material will compensate for small imperfections on the hard surface, leading to an effective seal. The materials forming the closure are pressed together by means of:

The other preferred form of closure system in pharmacy is heat-sealing. This usually achieves an effective and permanent seal, which can only be opened by destruction of part of the packaging material. An example is the glass ampoule, fused by heat. The fused glass forms a totally hermetic seal. Another example is the blister packaging of tablets. A multi-layered film of polymer material is preformed and filled with tablets, and sealed by heat and pressure to a thin aluminium strip foil.

A heat seal which can be peeled open is formed by materials which are not completely fused together. This can be achieved by the use of materials that are more or less incompatible [22, 24].

The design and manufacture of quality packaging materials is a science in itself. Container closure quality is essential and needs to be demonstrated as an integral part of the design of the medicinal product. This task can be most challenging when thousands of containers need to be reliably filled and closed on pharmaceutical packaging lines.

Many different procedures have been developed to test container closure quality:

The above list is not comprehensive and usually performance testing using selected tests will be sufficient. Many variations or combinations of these test methods can be made to tailor a particular packaging system. Testing is performed as part of the product development phase and can be a part of container and closure quality testing on incoming materials, or even production process monitoring. In small-scale production, it is recommended to request from the vendor any known data on container closure performance testing as a container system quality attribute. For any pharmaceutical application, it is wise to perform in-house testing of the container closure to validate the outcome of the packaging process. All that is needed is a balance and if possible some desiccant.

A bottle is a “container with a more or less pronounced neck and usually a flat bottom” [26].

Bottles may be used to package liquid preparations for a variety of administration routes:

Different administration routes lead to different requirements and different designs of bottles. These bottles will also require different closures and different delivery devices. This section describes the general characteristics of these bottles and the materials used to manufacture them. In Sects. 24.4.2, 24.4.3, 24.4.4, 24.4.5 and 24.4.6 some specific bottles are discussed. In Sect. 24.4.19 closures and delivery devices are discussed.