DMF, or their secondary amine degradants persist at an appreciable level into Stage 5?
2 Do traces of NaNO2 persist at an appreciable level through to Stage 7?
3 If yes to either Q1 or Q2, could a nitrosamine formed be expected to be present in the final API?
Figure 3.8 Process map of candesartan synthesis.
The use of purge assessments allows the adequate assessment of these questions.
Triethylamine is introduced into the synthesis at Stage 2 through its use as a base at stoichiometric quantities. However, following completion of the reaction, the crude product is obtained through concentration under full vacuum at 70–75 °C, which is able to remove the vast majority of the Et3N (boiling point 89 °C). While no measured data was available, a conservative estimate based on the volume reduction indicated a level of 5% Et3N for the crude product after concentration. This value (50 000 ppm) was therefore utilized as the starting concentration for the purpose of purge calculations (Figure 3.9 – step 2). The crude material then undergoes a range of unit processes to afford the clean intermediate 2 presenting a number of mechanisms of purge for Et3N. An initial extraction with HCl(aq) would result in formation of the corresponding salt (Et3N.HCl), which is known to be highly soluble in water and can therefore reasonably be expected to purge to a high degree (Purge factor [PF] = 10) based on solubility as a result of its ionizability (Figure 3.9 – step 3). However, a subsequent basic extraction would not result in a similar purge, as the dominant free base shows excellent solubility in both organic and aqueous solvents making the distribution more even. A purge of 1 is therefore the highest value that can be assigned, despite the likely removal of some Et3N in this process, to ensure a conservative prediction (Figure 3.9– step 4). Subsequent removal of the EtOAc (boiling point 77 °C) under reduced pressure will result in the co‐evaporation/azeotroping of triethylamine given the closeness of their respective boiling points. Utilizing the scoring system, a purge of 3 is scored for this step (Figure 3.9 – step 5), whereas the subsequent uptake and concentration in methanol (boiling point 66 °C) does not warrant application of purge as the boiling point of the triethylamine now exceeds 20 °C above that of the solvent (Figure 3.9 – step 6). Once again, this reiterates the conservative nature of the purge assignment, as some azeotroping is still likely to occur, particularly at reduced pressures where the difference in boiling points will contract to within 20 °C [14, 15]. Following precipitation and filtration of the intermediate, the Et3N that is both highly soluble in methanol and a liquid itself can safely be considered to remain extensively within the mother liquors. Additionally, the subsequent wash of the filter cake to remove residual mother liquors and surface impurities allows for a further cautious score of 10 based on solubility (Figure 3.9 – steps 6 and 7).
Figure 3.9 Breakdown of purge assignments for Et3N in the Stage 2 workup processes.
In the workup processes following Stages 3 and 4, the purge of Et3N is observed through similar mechanisms, reliant on the high degree of solubility in the process solvents and low boiling point. The total predicted purge for triethylamine up to the point of introduction of NaNO2 in Stage 5 is 8.1 × 108 against a required purge of 60 240 to achieve the 0.83 ppm limit for NDEA within the API. Utilizing the approach to reporting for Option 4 strategies developed by Barber et al., this corresponds to a purge ratio of 13 446 for Et3N (Figure 3.10). At this ratio very little justification would be necessary to demonstrate control of the impurity. In the scenario detailed here, the triethylamine is not the impurity of concern, but the nitrosamine NDEA that may be formed from it. Utilizing the same limit for the parent amine as for the nitrosamine imparts a further degree of conservatism, as quantitative conversion is hugely unlikely to occur, and therefore NDEA formation from Et3N is demonstrated to be well controlled and suitably de‐risked.
Figure 3.10 Purge calculation summary for Et3N.
A similar assessment was performed for both DMF (potential source of dimethylamine [DMA]) and the amines of concern, assuming their presence within the starting materials or from degradation (Figure 3.11). In each of these cases the degree of purge establishes the risk of carryover into Stage 5 to be low. In the case of DMF, which is approximated at a concentration of 200 000 ppm following the Stage 2 reaction, a target concentration of <1 ppm (below the 3 ppm limit for NDMA) and a predicted purge of 7.3 × 109 equates to a purge ratio of 36 500. This demonstrates the potential for NDMA formation, resulting from DMA formed by the degradation of DMF in Stage 5, to be insignificant and requiring minimal justification.
Figure 3.11 Purge calculation summary for DMF.
The purge appraisal of DMA and DEA highlights their greater propensity to be removed, primarily linked to their low boiling points (Figure 3.12). Determining a ratio for these impurities is difficult, as a starting concentration cannot be determined; however, they cannot be present in greater quantities than their parent structures and yet the potential for purge is far greater. As such, any purge ratio derived would be far in excess of those obtained for Et3N and DMF and therefore posing no appreciable risk to nitrosamine formation.
Figure 3.12 Purge calculation summary for DMA and DEA.
Purge calculations of amine‐related impurities within this synthesis has clearly demonstrated there to be no risk of formation of NDMA or NDEA within Stage 5, as the initial question has been answered – amine impurities and sodium nitrite are not present together within the same stage.
In order to fully de‐risk the formation of nitrosamines in the API, the formation of nitrosamines must also be considered within Stage 7, where both Et3N and DMF are reintroduced into the synthesis. Once again this can be assessed by considering the ability for carryover of one of the reacting components, in this case the NaNO2. The purge assessment of NaNO2 (Figure 3.13) indicated a high degree of purge in the two steps, with a predicted purge of 1 × 106. While the purge ratio for nitrite at this point is only 1, this