Evaluating Impurities in Drugs (Part II of III) - Pharmaceutical Technology

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Evaluating Impurities in Drugs (Part II of III)
In Part II of a three-part article, the authors examine impurities from chiral molecules, polymorphic contaminants, and genotoxic impurities.

Pharmaceutical Technology
Volume 36, Issue 3, pp. 58-72

Impurities due to the piperazine ring

The piperazine moiety is present in the chemical structure of more than 200 drugs. The biotransformation of the piperazine ring involves several well-known metabolic reactions, including N-oxidation, hydroxylation, N-dealkylation, and ring cleavages to N-substituted as well as N,N'-disubstituted ethylenediamines. In addition, several unexpected metabolic pathways have been reported for the piperazine ring: N-glucuronidation, N-sulfonation, formation of carbamoyl glucuronide, and glutathione adducts (61). Some compounds containing the piperazine ring indicate that the ring is normally metabolically stable when both nitrogen atoms are substituted with groups larger than ethyl.

Figure 2: The piperazine ring and metabolite impurities of olanzanpine. Ph. Eur. is European Pharmacopoeia. USP is US Pharmacopeia.
The lack of partial degradation of the piperazine ring to form ethylenediamine in olanzapine (2-methyl-4-(4-methyl-1-piperazinyl)10H-thieno[2,3-b][1,5]benzodiazepine) is slightly surprising. Some major metabolites were reported in humans plasma and urine, such as 4'-N-glucuronide and 4'-N-glucuronide (61, 62). Several other metabolites also were reported in mice, rats, monkeys, and dog urine (63). The ethylenediamine impurity, however, is not reported as a metabolite and a process impurity (see Figure 2).

When one of the nitrogen atoms is substituted by hydrogen on the piperazine ring, whether its methyl or ethyl, ethylenediamine formation is normally observed. An example is levofloxacin, S-(-)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid, which is the (S)-isomer of ofloxacin. In levofloxacin, the piperazine nitrogen atom is substituted with methyl due to several photodegradation impurities (see P 2 to P 10, Figure 3) (64–67). Some process impurities also are observed (see Figure 3). If the levofloxacin process involved methylenedichloride as a solvent, a chloro methyl impurity may form, and after isolation of the final product, the same impurity may convert to a di-quaternary cyclic piperazine impurity.

Figure 3: The piperazine ring and metabolite impurities of levofloxacin and ciprofloxacin. Ph. Eur. is European Pharmacopoeia and USP is US Pharmacopeia. CAS No. refers to Chemical Abstracts Service (CAS) number.
Additionally, when the ciprofloxacin (1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(piperazin-1-yl) quinoline-3-carboxylic acid) nitrogen atom is substituted by hydrogen on the piperazine ring, several metabolites and process impurities are formed (see Figure 3) (68–74). When nitrogen is substituted with hydrogen during the reaction, two dimer impurities (F-F dimer ciprofloxacin and F-Cl dimer ciprofloxacin) also are observed (75).


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