Chapter Six - Imatinib Mesylate

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Imatinib (INN), marketed by Novartis as Gleevec (United States) or Glivec (Europe/Australia/Latin America), received Food & Drug Administration (FDA) approval in May 2001 and is a tyrosine kinase inhibitor used in the treatment of multiple cancers, most notably Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia. Like all tyrosine kinase inhibitors, imatinib works by preventing a tyrosine kinase enzyme. Because the BCR-Abl tyrosine kinase enzyme exists only in cancer cells and not in healthy cells, imatinib works as a form of targeted therapy-only cancer cells are killed through the drug's action. In this regard, imatinib was one of the first cancer therapies to show the potential for such targeted action and is often cited as a paradigm for research in cancer therapeutics. This study presents a comprehensive profile of imatinib, including detailed nomenclature, formulae, physico-chemical properties, methods of preparation, and methods of analysis (including compendial, electrochemical, spectroscopic, and chromatographic methods of analysis). Spectroscopic and spectrometric analyses include UV/vis spectroscopy, vibrational spectroscopy, nuclear magnetic resonance spectrometry ((1)H and (13)C NMR), and mass spectrometry. Chromatographic methods of analyses include electrophoresis, thin layer chromatography, and high-performance liquid chromatography. Preliminary stability investigations for imatinib have established the main degradation pathways, for example, oxidation to N-oxide under oxidative stress conditions. Stability was also carried out for the formulation by exposing to different temperatures 0°C, ambient temperature, and 40°C. No remarkable change was found in the drug content of formulation. This indicates that the drug was stable at the above optimized formulation. Stability studies under acidic and alkaline conditions have established the following main degradation products: α-(4-Methyl-1-piperazinyl)-3'-{[4-(3-pyridyl)-2-pyrimidinyl] amino}-p-tolu-p-toluid-ide methanesulfonate and 4-(4-methylpiperazin-1-ylmethyl)-benzoic acid. The main degradation products under oxidation conditions, that is, 4-[(4-methyl-4-oxido-piperazin-1-yl)-methyl]-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-enzamide, 4-[(4-methyl-1-oxido-piperazin-1-yl)-methyl]-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide, and 4-[(4-methyl-1,4-dioxido-piperazin-1-yl)-methyl]-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-enzamide. Clinical application studies for pharmacodynamics, pharmacokinetics, mechanism of action, and clinical uses of the drug were also presented. Each of the above stages includes appropriate figures and tables. More than 50 references were given as proof of the above-mentioned studies.