Forced degradation study of abacavir sulfate under the frame of genotoxic impurity

Abstract

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. </span