**3.6.1 Dimeric impurity of cefotaxime**

The manufacturing and storage processes of cefotaxime produce various impurities such as dimeric impurity (Figure 2).

Fig. 2. Structure of the dimeric impurity of cefotaxime

The results of the mutagenesis assay indicate that the dimeric impurity is nonmutagenic to any test strains used in the presence and absence of S9 fraction. The results of the *in vitro* chromosomal assay show some chromosomal aberrations in cultured mammalian cells up to the maximum recommended concentration of 45 mg per culture, and no clastogenicity in mammalian cells *in vitro* (Agarwal *et al.*, 2004).

#### **3.6.2 Piperacillin impurity-A**

The piperacillin impurity-A is a prominent degradation product of piperacillin that appears during manufacturing and storage processes (Figure 3).

In all the strains of *S. typhimurium*; TA 97a, TA 98, TA 100, TA 102, and TA 1535, piperacillin impurity in the presence and absence of metabolic activation was found to be nonmutagenic. Also, *in vitro* chromosomal aberration assay did not reveal any significant alterations. It is found that piperacillin impurity-A up to 5 mg/ml is nonclastogenic to CHO cell lines in the presence and absence of metabolic activation (Vijayan *et al.*, 2007).

Tremogenic impurities comprise another sub-class of highly toxic impurities in APIs. Two pharmacopoeial APIs are known to have the potential to be contaminated with tremogenic impurities; pethidine and paroxetine (3-[(1, 3-benzodioxol-5-yloxy) methyl]-4-(4 fluorophenyl) piperidine). Pethidine can contain trace amounts of 1-methyl-4- phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) derived from the hydrolytic degradation of side chain. 4-(4- Fluorophenyl)-1-methyl-1,2,3,6-tetrahydropyridine (FMTP) can be a potential reactant/intermediate in the synthesis of paroxetine. Owing to their toxicity to cells in the *Substantia nigra*, these highly potent impurities can induce Parkinsonism in humans. Thus, these compounds are known toxic impurities; however their genotoxicity remains unclear

The following two impurities relate to the well known antibiotics cefotaxime and

The manufacturing and storage processes of cefotaxime produce various impurities such as

The results of the mutagenesis assay indicate that the dimeric impurity is nonmutagenic to any test strains used in the presence and absence of S9 fraction. The results of the *in vitro* chromosomal assay show some chromosomal aberrations in cultured mammalian cells up to the maximum recommended concentration of 45 mg per culture, and no clastogenicity in

The piperacillin impurity-A is a prominent degradation product of piperacillin that appears

In all the strains of *S. typhimurium*; TA 97a, TA 98, TA 100, TA 102, and TA 1535, piperacillin impurity in the presence and absence of metabolic activation was found to be nonmutagenic. Also, *in vitro* chromosomal aberration assay did not reveal any significant alterations. It is found that piperacillin impurity-A up to 5 mg/ml is nonclastogenic to CHO

cell lines in the presence and absence of metabolic activation (Vijayan *et al.*, 2007).

**3.5.4 Tremogenic impurities** 

(Borman *et al.*, 2008).

piperacillin.

**3.6 β-lactam related impurities** 

dimeric impurity (Figure 2).

**3.6.1 Dimeric impurity of cefotaxime** 

Fig. 2. Structure of the dimeric impurity of cefotaxime

during manufacturing and storage processes (Figure 3).

mammalian cells *in vitro* (Agarwal *et al.*, 2004).

**3.6.2 Piperacillin impurity-A** 

Fig. 3. Structure of piperacillin impurity-A
