Carry over of impurities - a detailed exemplification for glycopyrrolate

摘要

The original synthesis of glycopyrrolate (NVA237) was revised and shortened into an essentially one-pot process. Without isolating the intermediates, their purification became obsolete thereby increasing the possibility for the carry over of impurities. For that reason the actual, potential and theoretical impurities of the starting materials cyclopentyl mandelic acid and 1-methyl-pyrrolidin-3-ol as well as by-products which may occur during the synthesis were thoroughly investigated. Furthermore their transformations to possible impurities in the drug substance along the new synthetic route were performed in order to exclude them as actual impurities in the drug substance with certainty. The talk will highlight the underlying concepts, examples that they may not always work and the benefit of active collaboration with vendors. The results can simply be depicted in a single matrix to define the control strategy, a more generic representation of which is shown below.