Chloromethyl isopropyl carbonate (CMIC) is a raw material that is used to synthesize tenofovir disoproxil fumarate (TDF), an active pharmaceutical ingredient that is co-formulated with doravirine and lamivudine in the drug product DELSTRIGO™ to treat HIV. CMIC was found to be a potential mutagenic impurity, and needed to be controlled to 50 ppm or lower in the TDF drug substance. However, there are several challenges to developing a sensitive analytical method. For example, CMIC does not have a good chromophore, and it is difficult to achieve the desired sensitivity using HPLC-UV detection. Strong matrix interference (~1000x of 50 ppm CMIC) was observed in GC-FID analysis with direct injection. CMIC has a high boiling point, and it is difficult to achieve the desired sensitivity using headspace GC-FID. In this presentation, we will discuss the development of a simple GC-FID method with an LOQ of 10 ppm CMIC. A liquid/liquid extraction procedure was developed to selectively extract CMIC into the n-heptane layer while getting rid of all interference from TDF using an n-heptane: N,N-dimethylformamide (DMF)/water solvent system. This method has been successfully validated and transferred to multiple commercial sites to support process development and qualification.

Thinking outside of the box: Designing a simple solution to quantitate a mutagenic impurity in a complex matrix

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.