213-219<span style="font-size:
9.0pt;mso-bidi-font-size:8.0pt" lang="EN-US">Genotoxic impurities in drug substances or drug
products are growing concern to ensure public health. Genotoxic impurities
present in drug substances and drug products may be DNA reactive and can pose
significant problems for drug regulators and industry alike over several
decades. The principal concern related to drug safety is the prolong exposure
to compounds that can alter DNA, and may ultimately produce carcinogenicity.
Therefore, the practical issue to be addressed is that conventional procedures
should be available to identify DNA-reactive impurities in the shelf life of
drug product. In the present study, abacavir sulfate, an antiretroviral agent
is used to evaluate degradation pathways under different stress conditions in
order to identify degradation products as prescribed by ICH guidelines.
Abacavir sulfate is found to degrade under acidic and oxidative conditions
followed by formation of three degradation products which are separated by an
isocratic HPLC method. The degradation products are identified by LC-MS to
propose degradation pathways followed by evaluation of similarity with the
structural alerts for genotoxic impurities. Finally, characterization of the
genotoxic impurity can be achieved by FT-IR, NMR and LC-MS. Abacavir sulfate is
found to be stable to base hydrolysis and thermal treatment while susceptible
to degradation in oxidative stress and acidic hydrolysis. LC-MS study results
reveal that possible degradants are C8H10N6 (m/z
191.2) in acidic conditions whereas C14H18N6O3
(m/z 319.2) and C11H14N6O (m/z
247.2) in oxidative stress conditions. Structural alerts for pharmaceutical
impurities indicates the formations of N-hydroxyaryls and aza-aryl N-oxides
which may be genotoxic impurities.
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