Rubber closures

Several investigators have published research on incompatibilities of preservatives with rubber closures and other packaging components, particularly polymeric materials [11]. Again, challenging the product with selected microorganisms to measure bacteriostatic or bactericidal activity is necessary, including evaluation of efficacy as a function of time throughout the anticipated shelf life of the product. 

Bottles and vials are not subjected to such a vacuum test because of the flexibility of the rubber closure. However, bottles that are sealed under vacuum may be tested for vacuum by striking the base of the bottle sharply with the heel of the hand to produce a water hammer sound. Another test is the spark test, in which a probe is applied outside the bottle. When it reaches the air space of the bottle, a spark discharge occurs if the headspace is evacuated. 

H. Vromans and J. A. Van Laarhoven. Study on water permeation through rubber closures of injection vials. Int. J. Pharm., 79, 301 (1992). 

Pharmacopeial monographs do not set limits for additives, as they do for plastic polymers, and rubber closure (BP, Appendix XIX, USP (381)) tests are limited to... 

FIGURE 11 Influence of the solvent used for the Soxhlet extractions of two different commercial rubber closures (PI) and (P2) on the area of the chromatographic peaks of different classes of compounds detected in GC-MS [72]. 

Pikal, M. I, and Lang, J. E. (1978), Rubber closures as a source of haze in freeze-dried parenterals Test methodology for closure evaluation, J. Parent. Drug. Assoc., 32, 162-173. 

This same possibility exists with rubber closures, though not to the same degree. If the compounds sought in the sample are clearly not oil soluble, then lubricated stopcocks can be used. Olefins and aromatic compounds are generally more readily soluble and more easily lost under these circumstances than are saturated hydrocarbons or oxygenated compounds. 

Rubber closures are also known to absorb materials, including drugs. Absorption of preservatives such as chlorocresol into the rubber closures of injectable formulations has been studied extensively [13]. 

The water permeability of rubber closures used in injection vials is considered an important parameter in assessing the closures, but quantitative prediction of water permeability through rubber closures is difficult because the diffusion coefficient of water is dependent on relative humidity [14],... 

Jaehnke, R. W. O., Kreuter, J., and Ross, G. (1990), Interaction of rubber closures with powders for parenteral administration, / Parenteral sci. Tech., 44,282-288. 

G. H. Hopkins, Rubber closures for freeze-dried products. Dev. Biol. Stand. 36 139-144, 1977. 

The choice of materials available for long-term drug contact is very limited—borosilicate glass, bromobutyl or chlorobutyl rubber closures, certain inert polymers such as polytetrafluoroethylene (PTFE), tetrafluor-oethylene (TFE), and derivatives thereof, and stainless steels. Since the Code of Federal Regulations mandates that it be possible to inspect the drug product after filling, steel cannot be used as the primary drug container. In addition, polycarbonates, which would be ideal materials from durability, scratch-resistance, and cost perspectives, have very poor moisture vapor and extractables profiles. 

At the completion of the freeze-dry cycle, the partially inserted rubber closures are fully seated in the vials. The finished product contains a white or off-white sterile dry powder. 

Compression set is commonly used as a measure of the dimensional recovery of a rubber compound after compression at a defined level, usually 25%, at a specified time and temperature, usually 24 h at 70°C. High compression set values are associated with rubber that takes a set or loses its ability to spring back after compression. Low compression set is important for rubber closures and syringe plungers that are heat sterilized while under compression and remain under compression for long periods of time before use but must remain elastic and resilient to maintain seal integrity. Compression Set is measured on dimensionally defined test specimens. 

---