Drug stability is crucial in drug development since it affects the safety and efficiency of the drug product. Stability testing and identification of significant degradation products of the active pharmaceutical ingredient (API) are required during drug development. Long-term and accelerated stability testing is performed to provide an in-depth understanding of the stability of the active substance. Accelerated testing lasts 6 months and long-term testing lasts 12 months, which significantly prolongs the development of the drug product. Therefore, early prediction and identification of possible impurities in drug product is important in pharmaceutical development. Stress tests of the active substance can help in the early identification of possible degradation products, which helps to determine degradation pathways and intrinsic stability of the molecule. Stress tests also help to develop stability-indicating analytical methods. Before performing stress tests, we usually try to predict degradation products, using literature data and chemical knowledge. Increasingly, in silico tools that predict degradation products are used, which give us an initial picture of the stability of the molecule under different conditions. Such tools can also be helpful in identifying degradation products obtained in stress testing. Venetoclax is a selective inhibitor of the anti-apoptotic B-cell lymphoma (Bcl)-2 protein, a first of its kind. It was approved for the treatment of patients with chronic lymphocytic leukemia in the United States in 2016. Because venetoclax is a relatively new active substance, not much is known about its stability in the literature and no stability-indicating analytical method for venetoclax could be found. As the only Bcl-2 protein inhibitor on the market, it has a structure that differs from other known active substances. Thus, the stability of the molecule is also more difficult to predict at first glance. The purpose of our work was to determine the degradation products of venetoclax using a combined approach with in silico tools and stress tests, as well as to develop an analytical method for monitoring venetoclax and its degradation products. Additionally, we wanted to determine the degradation pathways and degradation chemistry of venetoclax based on the structures of degradation products. The aim was also to include the principles of Analytical Quality by Design (AQbD) in analytical method development, thus improve the robustness of the analytical method, and better understand the effects of critical method parameters on the critical method attributes.
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