Characterization of imatinib mesylate formulations distributed in South American countries: Determination of genotoxic impurities by UHPLC–MS/MS and dissolution profile

Abstract

Imatinib mesylate (IM) is an anti-neoplasic drug used for the treatment of cancer. Recent new guidelines specify daily doses and concentration limits for genotoxic impurities (GTIs) in pharmaceutical final products. Therefore, in this work an analytical method using UHPLC-MS/MS was developed, validated and applied to characterize IM tablets for two GTIs: N-(2-methyl-5-aminophenyl)-4-(3-pyridyl)-2-pyrimidine amine (Imp. 1), and N-[4-methyl-3-(4-methyl-3-yl-pyrimidin-2-ylamino)-phenyl]-4- chloromethyl benzamide (Imp. 2), simultaneously. Additionally, dissolution data of IM tablets were compared using a methodology recommended by the US Food and Drug Administration. The UHPLC method utilized an Acquity BEH C (150 × 2.1 mm, 1.7 μm) maintained at 40°C. The mobile phase consisted of ammonium formate 0.063% (phase A) and acetonitrile plus 0.05% formic acid (phase B) in gradient elution. A sensitive method for determination of previously mentioned GTIs in IM tablets was successfully developed and applied. Overall, the formulations analyzed in this work showed low levels of Imp. 1 and Imp. 2. However, the sample named D1 showed very high levels of Imp. 1 and failed to meet the requirements established by the US Food and Drug Administration for dissolution data. Periodic verification of GTIs in pharmaceutical formulations is important to minimize safety risks, so analytical methods to determine it need be available and implemented in routine analysis.

Method Development, Validation and Degradation Studies of Imatinib Mesylate by UPLC

“…The purpose of stability testing is to provide evidence on how the quality of a drug substance varies with time under the influence of a variety of environmental factors such as temperature, oxidation, and light, which enables establishing shelf life recommended by the International Conference on Harmonization (ICH) guidelines [3]. Literature survey revealed for few analytical methods reported in the estimation of imatinib mesylate in bulk and pharmaceutical dosage form [4][5][6][7][8][9][10][11][12]. The current study aimed to develop a faster chromatographic technique a simple, specific, precise, and accurate reverse-phase ultra-performance liquid chromatography (UPLC) that can result in shorter analysis times without compromising on the resolution and sensitivity.The imatinib mesylate chemical structure was shown in Fig.…”