Nelson Labs Europe, a leading lab in providing extractables and leachables services for the pharmaceutical industry, has developed a procedure to obtain and analyze the pure rubber oligomers C13H24 and C21H40 from rubber extracts.
The procedure to obtain the C13H24 and C21H40 oligomers can be considered as a crucial first step in synthesizing the brominated oligomers C13H23Br and C21H39Br, which are considered as potential mutagenic compounds.
What were the drivers to develop a procedure in order to obtain the pure rubber oligomeric compounds?
- All pharmaceutical butylrubbers (butyl, chlorobutyl, bromobutyl) do contain the C13H24 and C21H40 oligomers as impurities.
- Extractable and subsequent leachable studies have revealed, in certain cases, that C13H24 and C21H40 oligomers may leach out of the rubber into the drug product.
- For the C13H24 oligomer, limited scientific work has been performed to elucidate its chemical structure (NMR).
- For the C21H40 oligomer, however, the chemical structure had not yet been determined experimentally. A structure was postulated, based upon the potential formation pathways from a butyl rubber.
- No scientific/experimental data has yet become available regarding the toxicity of these compounds.
What has been accomplished and what will be the impact of these analytical standards for C13H24 and C21H40 on the overall risk assessments for pharmaceutical rubbers?
- After almost two years of research, the R&D team at Nelson Labs Europe has finally developed a procedure to isolate these compounds from rubber extracts via a. o. preparative chromatography.
- Both the C13H24 and the C21H40 oligomers were obtained with a purity of >90%.
- The chemical structures of both oligomers have been determined (NMR/HR-MS).
- The chemical structures of C13H24 and C21H40 can finally be included in each report of an extractable or leachable study performed on butyl, chlorobutyl, or bromobutyl rubbers.
- For the first time ever, the chemical standards for C13H24 and C21H40 can be used to perform accurate concentration measurements of these compounds as a leachable in the drug product.
- The C13H24 and C21H40 compounds are now included in the Proprietary Compound Screener Database in order to allow a rapid identification of the compounds when performing impurities testing or extractables testing.
- Nelson Labs Europe is preparing to perform AMES testing on both compounds in order to further evaluate their potential for mutagenicity.
- The results of the AMES tests will allow Nelson Labs Europe to monitor these compounds as leachables in drug products at appropriate threshold levels.
Future developments: Obtaining the brominated oligomers C13H23Br and C21H39Br.
- Nelson Labs Europe is developing a “Modified AMES” test to determine the mutagenicity of extracts of materials, obtained in a Controlled Extraction Study (CES).
- Preliminary results of this “Modified AMES” test have shown that CES extracts of bromobutyl rubbers are testing AMES positive, even at a mild extraction ratio, with a clear dose-response effect.
- Structure Activity Relationship (SAR) assessments on the extractable compounds of a bromobutyl rubber have shown that the brominated oligomers C13H23Br and C21H39Br are compounds with mutagenic potential.
- Obtaining the brominated oligomers will allow Nelson Labs Europe to perform an AMES test (OECD 471) on both brominated oligomers in order to verify the presumptions of the mutagenicity potential related to these compounds.
- If the AMES test confirms the conclusions of the SAR assessments, already performed on these compounds, it will be very likely that these compounds will need to be controlled as leachables at lower threshold levels.
- Having access to the brominated oligomeric standards C13H23Br and C21H39Br will allow Nelson Labs Europe to determine the presence and level of these compounds, leached from the rubbers into the drug product, at appropriate low threshold levels.
- The brominated oligomers are expected to be available at Nelson Labs Europe in Q3 of 2012.