Module 3 - Strategic case studies in practice

manufacturing processes for aminophenazone conducted at that time, the use of sodium nitrite for nitrosation seems to be unavoidable for synthesis of the intermediate 4-Amino-2,3-dimethyl-1- phenylpyrazol-5-one ("Aminoantipyrin") at first sight. However, this intermediate was synthesized via nitration and subsequent hydrogenation processes previously [Thoms et al. (1923); Waser, E., (1925); Hamel et al. (1970) and recently Amanchi et al. (2019)]. Table 2.2.2.5.1-1 Critical Compound Combinations responsible for N -nitrosamine formation in aminophenazone

N -Nitrosamine

NOX Source

Amine Source

Amine nitrosated by NOX

Critical Compound Combination

N H DMA and/or N

N

O

N N

O N N

NDMA

NaNO 2

reagent/API

O N N

aminophenazone

aminophenazone

2.2.2.5.2. Further historical literature data on potential root causes

Following the aminophenazone findings, investigation of N- nitrosamine impurities in other APIs and FPs was performed. In contrast to aminophenazone, [Eisenbrand et al. (1979)], Krull et al. (1979) found none of the 73 products tested within their study to contain NDMA. However, N- nitrosamine levels were detected in disulfiram FP, ranging from 94 – 980 ppb for NDEA [Castegnaro et al. (1981)] and in piperazine formulations, up to 20 ppm mononitroso-piperazine [Bellander et al. (1985)]. Concentration ranges in APIs and FP were described in the following publications Castegnaro et al. (1981); Taylor et al. (1980); Dawson et al. (1987); Bellander et al. (1985). The chemical structures of APIs reported in literature to contain NDMA are shown in figure 2.2.2.5.2-1 [Parr et al. (2019)].

EMA/369136/2020

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