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.
Colistin, used as a last-resort drug, has a narrow therapeutic range that justifies therapeutic drug monitoring. Few data are available in the literature regarding the in vivo unbound fraction of colistin. The objectives of this study were to develop a method to isolate unbound colistin in clinical samples by ultrafiltration and to quantify it. The association between unbound colistin and biological parameters (total protein, albumin, alpha-1-acid glycoprotein and creatinine) was investigated. The measured ranges were 0.036-7.160 mg/L for colistin A and 0.064-9.630 mg/L for colistin B. The process of isolation and determination of unbound colistin was applied to clinical samples (n = 30) within 40 min and no non-specific binding was observed during the ultracentrifugation step. The median unbound fractions of colistin measured were 34.3% (12.8-51.0%) and 53.4% (27.0-77.8%) for colistin A and B, respectively. High interindividual biological variation of binding was observed for colistin A and B that was not explained by the biochemical parameters studied. The method developed could be useful to improve outcomes for patients.
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