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Monitoring and Control of Genotoxic Impurity Acetamide in the Synthesis of Zaurategrast Sulfate
journal contribution
posted on 2010-07-16, 00:00 authored by Arnaud Schülé, Célal Ates, Magali Palacio, Jimmy Stofferis, Jean-Pierre Delatinne, Bruno Martin, Steven LloydIn this article we describe the strategy adopted to minimize the
risk of acetamide presence in zaurategrast sulfate drug candidate.
A risk of acetamide formation (a potential genotoxic impurity) was
identified in the API formation step of the process during the early
development phase. In order to keep the project development timelines
unchanged and without having the appropriate analytical method ready
developed, we chose to minimize the risk of acetamide impurity presence
by applying an adequate chemical process design. The implementation
of a workup sequence involving initially three aqueous washes was
later proven to be successful when an appropriate analytical method
to detect acetamide below ppm levels was available. Additionally the
analytical tool gave us the opportunity to assess and fine-tune the
designed process for acetamide elimination by spiking experiments.
Data acquired during this evaluation showed that a single aqueous
wash associated with two efficient crystallization steps were finally
enough to deliver API with a content of acetamide below the level
defined as the acceptance criterion.
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acetamide formationcrystallization stepsZaurategrast SulfateInacetamide impurity presenceproject development timelinesacceptance criterionppm levelsdevelopment phaseAPI formation stepspiking experimentsworkup sequenceacetamide presencechemical process designzaurategrast sulfate drug candidateGenotoxic Impurity Acetamidegenotoxic impurityacetamide elimination