Bromobutyl rubber oligomers

Bromobutyl rubber is an excellent choice for pharmaceutical stoppers and seals applications due to low levels of additives and impurities, high impermeability to moisture and air, chemical and biological inertness, resistance to aging and heat sterilization, and easiness to vulcanize using low levels of ‘clean’ curatives. However, outstanding physical and chemical properties come with a price. Bromobutyl rubber is derived from combining butyl rubber with bromine. During bromination of elastomers, the low molecular weight oligomers C13H24 (CAS: 63251-38-7) and C21H40 (CAS: 114123-73-8), which are always present in butyl rubbers, are converted partially into their brominated versions, C13H23Br and C21H39Br (see a typical chromatogram of bromobutyl rubber stopper extract). These bromo alkenes might affect the quality of pharmaceuticals when bromobutyl rubber is used as a material for the container-closure system.

Figure 1. Typical GC-MS chromatogram of an isopropanol-water extract of bromobutyl rubber stopper. The labeled peaks indicate the presence of brominated and non-brominated elastomer oligomers.

Figure 1. Typical GC-MS chromatogram of an isopropanol-water extract of bromobutyl rubber stopper. The labeled peaks indicate the presence of brominated and non-brominated elastomer oligomers.

In the next section, you will learn why the migration of brominated rubber oligomers, C13H23Br and C21H39Br, into drug products should be monitored.

Why C13H23Br and C21H39Br leachables must be under control

It is necessary to establish that the packaging system used to store any pharmaceutical product is not leaching substances that may negatively affect its safety and efficacy.

There are two potential issues that the Br-C13 and Br-C21 substances might cause when they migrate into the drug product: their carcinogenicity/mutagenicity and reactivity with drug products.

C13H23Br and C21H39Br are potentially mutagens

As it can be seen from the structures of the Br-C13 and Br-C21 compounds, they belong to the class of aliphatic halogens. The Toxtree software triggers a structural alarm for mutagenicity because aliphatic halogens are alkylating agents and might damage DNA.

Figure 1. Typical GC-MS chromatogram of an isopropanol-water extract of bromobutyl rubber stopper. The labeled peaks indicate the presence of brominated and non-brominated elastomer oligomers.

Figure 2. Structure of the Br-C13 rubber oligomer

Figure 1. Typical GC-MS chromatogram of an isopropanol-water extract of bromobutyl rubber stopper. The labeled peaks indicate the presence of brominated and non-brominated elastomer oligomers.

Figure 3. Structure of one of the Br-C21 isomers

C13H23Br and C21H39Br are reactive leachables

However, it is not only DNA that can react with the brominated rubber oligomers. If the API molecule contains nucleophilic centers, C13H23Br and C21H39Br can alkylate them reducing the efficacy of the drug and generating impurities. For example, it has been shown that C13H23Br reacts with lyophilized insulin  (watch this video https://www.youtube.com/watch?v=0B6nHWMZIXE at 23rd min).

How to monitor  brominated rubber oligomers, C13H23Br and C21H39Br

The brominated rubber oligomers can be analyzed by GC-MS-based methods. Previously, the corresponding reference standards have not been available on the marked and surrogate standards have been employed for the determination of oligomeric rubber extractables and leachables. However surrogate substances do not provide an exact response match for the target analytes. Only authentical reference standards can guarantee the precision of the analysis.

Brominated rubber oligomers, C13H23Br and C21H39Br, are now available at Vit-n-Vivo

We at Vit-n-Vivo were able to isolate rubber oligomers and are offering now four reference materials: C13H23Br rubber oligomer, C21H39Br rubber oligomer (RI 2030), the mixture of C21H39Br rubber oligomers (RI 1985 and 1990), as well as C21H40 (CAS: 114123-73-8) rubber oligomer.

Figure 1. Typical GC-MS chromatogram of an isopropanol-water extract of bromobutyl rubber stopper. The labeled peaks indicate the presence of brominated and non-brominated elastomer oligomers.

Figure 7. Structure of C21 non-brominated rubber oligomer

Figure 1. Typical GC-MS chromatogram of an isopropanol-water extract of bromobutyl rubber stopper. The labeled peaks indicate the presence of brominated and non-brominated elastomer oligomers.

Figure 4. Mass spectrum of C13H23Br rubber oligomer

Figure 1. Typical GC-MS chromatogram of an isopropanol-water extract of bromobutyl rubber stopper. The labeled peaks indicate the presence of brominated and non-brominated elastomer oligomers.

Figure 5. Mass spectrum of C21H39Br-A compound (RI 1985)

Figure 1. Typical GC-MS chromatogram of an isopropanol-water extract of bromobutyl rubber stopper. The labeled peaks indicate the presence of brominated and non-brominated elastomer oligomers.

Figure 6. Mass spectrum of C21H39Br compound (RI 2030)