Abstract
Degradation pathway for bortezomib is established as per ICH recommendations by validated and stability indicating reverse phase liquid chromatographic method. Bortezomib is subjected to stress conditions of acid, base, oxidation, thermal and photolysis. Significant degradation is observed in acid and base stress conditions. Five impurities are studied and the major degradant (RRT about 1.19) was identified by LC-MS and spectral analysis. The stress samples are assayed against a qualified reference standard and the mass balance is found close to 99.5%. Efficient chromatographic separation is achieved on a Shim pack XR-ODS-II(100X3 mmx2.2 μm) stationary phase with simple mobile phase combination delivered in gradient mode and quantification is carried at 270 nm at a flow rate of 0.6 mL min. In the developed LC method the resolution between bortezomib and five potential impurities (imp-1, imp-2, imp-3, imp-4 and imp-5) is found to be greater than 2.0. Regression analysis shows an r value (correlation coefficient) of greater than 0.999 for bortezomib and five potential impurities. This method is capable to detect the impurities of bortezomib at a level of 0.020 % with respect to test concentration of 2.0 mg mL for an 8-μL injection volume. The developed rapid LC method is validated with respect to specificity, linearity & range, accuracy, precision and robustness for impurities determination.
Highlights
Bortezomib, (R)-3-methyl-1-((S)- 3-phenyl-2-(pyrazine-2-car boxamido) propanamido) butyl-boronic acid, is one of the most important members of a new class of drugs, containing a boronic acid moiety, effective on a wide group of tumors. It is mainly used for the treatment of multiple myeloma, a plasma cell tumor which accounts for 10% of all blood system malignancies
Peak purity test results derived from the photo diode array detector (PDA) detector confirmed that the bortezomib peak and the degraded peaks are homogeneous and pure in all of the analyzed stress samples
The assay of bortezomib is unaffected by the presence of imp-1, imp-2, Stress condition
Summary
Bortezomib, (R)-3-methyl-1-((S)- 3-phenyl-2-(pyrazine-2-car boxamido) propanamido) butyl-boronic acid, is one of the most important members of a new class of drugs, containing a boronic acid moiety, effective on a wide group of tumors. At present, it is mainly used for the treatment of multiple myeloma, a plasma cell tumor which accounts for 10% of all blood system malignancies. Bortezomib is commercialized by Millennium Pharmaceuticals (Mass, USA) in the US and Janssen-Cilag in Europe under the trade name Velcade, and is administered as intravenous bolus [1,2,3,4,5]. One method appeared “Stability-indicating RPHPLC method for analysis of bortezomib in a pharmaceutical dosage form” [7] (Table 4)
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