Genotoxic impurities (GTI’s) are intermediate, reactive products or degradants formed during the synthesis of drug substance, formulation of the drug product, or storage of drug substance or drug product. Genotoxic impurities have the potential to directly cause DNA damage when present at low levels leading to mutations and therefore, potentially causing cancer.
Chemical structures are helpful to plan to classify compounds into their types that will alert them to potential material. The computer software’s e.g., MultiCASE’s M case, Accelrys’s Topcat, or LHASA’s DEREK is available for forecasting the probable toxicity of drug impurities on the basis of it is chemical structure. It is predictive and may not be factual, they will give hint of which one would be confirmed from the toxicity studies. Performing Ames bacterial mutagenicity testing after software provides a structural alert. Results from the Ames test are considered more definitive than the in silico data.
There are number of structural subjects that give surge to alkylating capability and these are further sub-categorised below.
These include alkyl chlorides bromides and iodides. Reactivities are in the order I > Br > Cl. Hence iodide salts are sometimes used to catalyse a reaction with alkyl chlorides, since I is a good nucleophile that displaces the chloride. The resulting alkyl iodide is a more powerful alkylating agent because iodide is a much better leaving group than chloride.
2. Hydroperoxides: Hydroperoxides result in oxidative damage to DNA.
3. Fused tricyclics: These compounds are able to intercalate between the coils of the DNA double helix.
4.Substituted purines and pyrimidines: Replaced purines and pyrimidines can themselves be inaccurately merged into the DNA sequence, leading to mutations.
5.Epoxides: Ring-opening of epoxide results in a reactive ion that can alkylate DNAQuinolines can be metabolished to form an epoxide on the nitrogen ring.
6.Aziridines: The strained ring in aziridines makes them reactive, with ring-opening under attack from any nucleophile to create a new nucleophile–carbon bond. Aziridine rings can be formed from the intramolecular substitution of a halogen atom by the nitrogen in nitrogen mustards.
7.Reactive amines: Aromatic amines (anilines) can be activated in vivo to form reactive amines. These are nucleophiles and may attack DNA, forming covalent modifications. Aromatic nitro compounds can be metabolized and form reactive amines.
Chemical structure with listed functional groups known to be involved in reactions with DNA that could be used as structural alerts. These functional groups were categorized into aromatic groups. These are reported as genotoxic impurities which should be removed or in cases where it is inevitable, these should be within limits to prevent the toxicity. Need to develop different API purification techniques for removal of genotoxic impurities to the stringent levels.