Knowledge of the active pharmaceutical ingredient (API) properties, including the stability of the API in different micro-environments, is important for the development of an effective, safe and quality medicinal product. The appropriate quality of the API is ensured by setting a specification of the API, which should also contain a list of impurities. Degradation products during normal storage usually occur at very low concentrations, therefore, to obtain large quantities of degradation products in the early stages of development, stress stability testing is performed. Before carrying out stress stability testing, we try to predict potential degradation products using literature data and chemical knowledge, and more recently also in silico tools for predicting degradation products.
Cabotegravir is a new API from the group of viral integrase inhibitors. There was no data on its stability available in the literature, nor was an analytical method available to determine cabotegravir assay and determination of its impurities.
The purpose of our research was to determine the degradation products of cabotegravir by conducting stress tests of the API, using in silico tools for predicting degradation products and developing an analytical method using the AQbD principles for determining of cabotegravir assay and determination of its impurities. We also aimed to determine the degradation mechanisms of cabotegravir under different micro-environmental conditions based on the determined structures of isolated cabotegravir degradation products.
The Introduction, that consists of two introductory chapters presents available knowledge in the field of cabotegravir until the beginning of our research and the basics of the development of analytical methods using AQbD principles.
In the first chapter of the research work, the performance of stress tests, the isolation and determination of the structures of the main degradation products of the cabotegravir are presented. Based on the structures of the isolated degradation products, we defined the main degradation pathways of cabotegravir under acidic and oxidative conditions and based on different additional studies proposed degradation mechanisms of cabotegravir.
The second chapter of the research work describes the development of an AQbD analytical method for the determination of cabotegravir assay and its eight impurities. We performed initial screening, optimization and robustness testing of the method. Based on the results and the mathematical models obtained, we determined the method operating design room (MODR) within which we defined the method's optimal operating point. A validation of the analytical method was performed at that point.
Chapter 3 presents the application of the in silico tool Zeneth in a case study of cabotegravir API degradation. In the case of cabotegravir, in silico prediction of the degradation products was not successful as the software did not predict any of the four isolated cabotegravir degradation products. The results of the cabotegravir degradation study that have been made public can help to expand the knowledge library of in silico tools and thereby improve the predictive power of degradation product prediction tools.
|
