Module 3 - Strategic case studies in practice

A typical drawback of these azide reagents and azide reagent /catalyst combinations is that upon hydrolytic work-up under acidic conditions, required for isolation and extraction of acidic tetrazoles, hazardous hydrazoic acid is liberated [Wittenberger, S. J., (1994)]. Residual quantities of azide reagents can be decomposed to gaseous by-products such as nitrogen (N 2 ) and dinitrogen oxide (N 2 O) by the addition of sodium nitrite (NaNO 2 ), as recommended for mother liquors in the industrial production of sodium azide [Bräse et al. (2015)]. Considering that for sartans, azide reagents are used typically in excess, at least equimolar quantities of sodium nitrite in relation to the azide reagent are required to enable complete depletion by redox reaction.

Figure 2.2.2.2-2 Depletion of hydrazoic acid by sodium nitrite [Bräse et al. (2015)]. In contrast, active substance manufacturers did not make use of the option to deplete -in turn- residual nitrite levels by addition of more or less non-toxic reducing agents such as e.g. urea and amidosulfonic acid [Laue et al. (2013)].

Figure 2.2.2.2-3 Depletion of nitrite by urea and amidosulfonic acid [Laue et al. (2013]. In principle, quenching procedures in the cyclization step of sartan processes can be performed in the presence or in the absence of APIs and intermediates, i.e. after phase separation of liquids or after separation of solids from the mother liquor by filtration. Quenching procedures in the presence of product (i.e. before separation procedures) enhance process safety but possess concomitantly the risk of significant by-product formation. In contrast, quenching procedures in the absence of product (i.e. after separation procedures) bear an inherent process safety risk but reduce the risk of deleterious side reactions with the product significantly. Any re-extraction or concentration followed by precipitation/crystallization from the quenched mother liquor to increase the overall yield of the process step can also lead to an elevated contamination of product with by-products formed during the quenching operation. According to the CHMP Assessment Report for the sartans referral 4 , different solvents, reagents and catalysts were used in the tetrazole forming cyclization step. Toluene, xylene, DMF and NMP as well as corresponding solvent mixtures (also with water and alcohols) were selected as high boiling solvents for the cyclization reaction, while products were often extracted with co-solvents such as EtOAc, CH 2 Cl 2 during working-up procedures. In addition to tributyltin azide, sodium azide alone or in combination with tributyltin chloride and bis(tributyltin)oxide [(Bu 3 Sn) 2 O] were frequently chosen as the azide source. Some processes required the addition of auxiliary bases such as triethylamine (TEA) and diisopropylethylamine (DIPEA). Zinc bromide (ZnBr 2 ), triethylammonium chloride (TEA HCl), and tetrabutylammonium bromide (TBAB) represented typical catalysts to accelerate reaction rates. During review of API manufacturing data, it became evident that NaNO 2 was added only in the minority of cases, i.e. mostly in large manufacturing processes. Regarding manufacturing processes for tetrazole-containing sartans, this reagent is not required in the cyclization step, but used only for

4 https://www.ema.europa.eu/en/documents/variation-report/sartans-article-31-referral-chmp-assessment-report_en.pdf

EMA/369136/2020

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