Abstract
A novel, simple, sensitive, stability indicating HPLC method was developed and validated for quantification of impurities (process related and degradants) and assay determination of bortezomib. Stability indicating power of the method was established by forced degradation experiments and mass balance study. The chromatographic separation was achieved with Waters SymmetryShield RP18 column using gradient elution using the mobile phase-A consists of a mixture of water-acetonitrile-formic acid (715 : 285 : 1, v/v/v) and the mobile phase-B consists a mixture of methanol-water-formic acid (800 : 200 : 1, v/v/v), respectively. The developed method is validated for parameters like precision, accuracy, linearity, LOD, LOQ, and ruggedness. Central composite experimental design (CCD) was applied to check the robustness of the method. The stability tests were also performed on drug substances as per ICH norms.
Highlights
Bortezomib [(1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl]boronic acid] is a potent first-in-class dipeptidyl boronic acid proteasome inhibitor [1,2,3,4,5,6] that was approved in May 2003 in the United States for the treatment of patients with relapsed multiple myeloma where the disease is refractory to conventional lines of therapy
A few publications are available for bortezomib, some of are available on [7, 8] stability and characterization of bortezomib and metabolites observed in human plasma with the help of MDS sciex API 3000 triple quadruple LC MS using turbo ion spray interface set at 325C and [9] enhanced delivery of cisplatin to international ovarian carcinomas mediated by the effects of bortezomib on human copper transporter and [10] one of it is in human plasma using LC MS
An exhaustive study on the stability of bortezomib is demanding as the current International Conference on Harmonisation (ICH) guidelines require that stability analysis should be done by using stability-indicating methods, developed, and validated after stress testing on the drug under a variety of conditions, including hydrolysis, oxidation, photolysis, Chromatography Research International and thermal degradation [11,12,13,14,15]
Summary
Bortezomib [(1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl]boronic acid] is a potent first-in-class dipeptidyl boronic acid proteasome inhibitor [1,2,3,4,5,6] that was approved in May 2003 in the United States for the treatment of patients with relapsed multiple myeloma where the disease is refractory to conventional lines of therapy. Extensive literature survey reveals there is no stability-indicating LC method for determination of related substances and for quantitative estimation of bortezomib in bulk drugs. An exhaustive study on the stability of bortezomib is demanding as the current International Conference on Harmonisation (ICH) guidelines require that stability analysis should be done by using stability-indicating methods, developed, and validated after stress testing on the drug under a variety of conditions, including hydrolysis (at various pH), oxidation, photolysis, Chromatography Research International and thermal degradation [11,12,13,14,15]. The structural characterization and synthesis of the degradation products allow both to establish the degradation pathways and their quantitative determination in drug substance. In the present work, the chemical degradation pathways of bortezomib were established through a forced degradation study and a selective, precise, and accurate LC method for simultaneous estimation of bortezomib and its degradation products was developed. The validation of the proposed method was carried out and its applicability was evaluated in commercial form analysis
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