Abstract
Venetoclax is an emerging drug for the treatment of various types of blood cancers. It was first approved in 2016 for the treatment of relapsed and refractory chronic lymphocytic leukemia. Later, the indications expanded, and multiple research as well as clinical studies are still conducted involving venetoclax. No analytical method for the determination of venetoclax can currently be found in the literature. We developed a mass spectrometry-compatible stability-indicating ultrahigh-performance liquid chromatography (LC) method for venetoclax. The LC method was developed using analytical quality by design principles. The developed method is able to separate venetoclax and its degradation products. The method was validated in the working point where a linearity range was established and accuracy, repeatability, and selectivity were assessed. Venetoclax is the only Bcl-2 protein inhibitor on the market. It is very effective in combinational therapy, so future drug development involving venetoclax may be expected. A stability-indicating method could aid in the development of new pharmaceutical products with venetoclax.
Highlights
Venetoclax (4-[4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexen-1-yl]methyl]piperazin-1-yl]-N-[3-nitro-4-(oxan-4ylmethylamino)phenyl]sulfonyl-2-(1H-pyrrolo[2,3-b]pyridin5-yloxy)benzamide) (Figure 1) is an orally bioavailable, B-cell lymphoma-2 (Bcl-2) selective inhibitor.[1]
We wanted to maximize the amount of water in the solvent so as to minimize the solvent elution effect in the liquid chromatography, which can result in a poor peak shape
ACN-dimethyl sulfoxide (DMSO)-buffer (7:2:1, v/v/v) was used as a solvent, but it was later changed for ACN-DMSO-buffer (6:3:1, v/v/v) after precipitation was observed in the vial after 2 months of storage at 5 °C
Summary
Venetoclax (4-[4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexen-1-yl]methyl]piperazin-1-yl]-N-[3-nitro-4-(oxan-4ylmethylamino)phenyl]sulfonyl-2-(1H-pyrrolo[2,3-b]pyridin5-yloxy)benzamide) (Figure 1) is an orally bioavailable, B-cell lymphoma-2 (Bcl-2) selective inhibitor.[1]. EMA approved venetoclax for the treatment of patients with genetic changes that make them unsuitable for chemoimmunotherapy when B-cell-receptor-pathway inhibitors (such as ibrutinib and idelalisib) are not suitable or have failed and for the treatment of patients without these genetic changes after treatments with chemoimmunotherapy and a Bcell-receptor-pathway inhibitor have both failed. EMA approved venetoclax in combination with rituximab in patients who have received at least one previous treatment. The use of venetoclax in numerous other indications is still being explored. Venetoclax has shown to be effective in Received: May 19, 2020 Accepted: June 24, 2020 Published: July 9, 2020
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