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Stage 1a and 1b products are generally telescoped through into the Stage 4 process; however, to understand likely levels of the alkyl bromide 2 that might be present, a sample was removed from Stage 1a and the reaction solvent removed under vacuum.¹⁰ Subsequent evaluation by ¹H NMR (Figure 3.5) confirmed that the alkyl bromide 2 was present at <5% molar ratio (m/m) within this product, rather than the initial conservative estimate of 100% molar ratio based on the 1 molar equivalents excess used for this reagent. This observation aligns with the formation of polymer and allows a more realistic purge prediction to be estimated based on “point of last measurement.” Substituting a residual level of ethyl bromoisobutyrate of 5% (50 000 μg/g) into the Stage 4 process, we can now estimate that the predicted purge factor for Stages 4a, 4b, and 5 is 1 × 10⁵ with a required purge factor of 20 (50 000/2500 = 20), which gives a purge ratio of 5000 and fully justifies an ICH M7 [8] Option 4 control. While not necessarily required, checking the ¹H NMR of the crude GW641597X (Stage 4b product) confirmed that alkyl bromide 2 is not detected, helping to further validate the predicted purge factor.

Figure 3.5 ¹H NMR of Stage 1a product 3.