A mechanistic approach was undertaken to understand the oxygen sensitivity of a Pd-catalyzed amination reaction used in the synthesis of an active pharmaceutical ingredient. FlowNMR and dissolved oxygen probes were used as process analytical technology alongside kinetic and unit operation models to better characterize the oxidative deactivation pathways of the catalyst. Interplay between ligand excess, oxygen inertion, and additional degassing due to reflux were all found to contribute to reaction rate variability. This mechanistic approach allowed for appreciation and clear communication of the risks, development of protocols to mitigate those risks, and successful scale-up under rapid development timelines.
The ICH M7 guidance provides a series of flexible control options for the control of (potentially) mutagenic impurities (PMIs) that fully align with key risk-based principles. This includes option 4, which leverages existing process knowledge and/or data to justify control of PMIs without the need for routine analytical release testing during manufacturing. One such technique highlighted uses systematic, semiquantitative calculations to define the degree of "purge" of PMIs within a synthetic route to an active pharmaceutical ingredient (API) based on physicochemical properties of the impurities in question, and the manufacturing process being undertaken. This paper introduces a consortium-led initiative, Mirabilis, which aims to build on the semiquantitative purge approach, and harmonize industry best practices by enabling the calculations to be conducted in a standardized, consistent, and reproducible manner. The development of an expert-derived knowledge base for the prediction of reactivity by enhancing expert opinion using evidence derived from the published literature and experimental data is also discussed. Furthermore, this paper describes the application of Mirabilis software for the processes involved in the synthesis of verubecestat, naloxegol oxalate, and camicinal.
The impact of several new technologies on the development of a manufacturing process for LY518674 is described. Extensive use of process analytical technology (PAT) throughout development, both at laboratory and pilot-plant scale, enabled data-rich experiments, shortened development cycle times, and obviated the requirement of PAT for process control at larger scale. In situ ReactIR was used to develop a kinetic model for a one-pot preparation of a semicarbazide intermediate. Parallel crystallizers fitted with online focused-beam reflectance measurement (FBRM) and particle vision and measurement (PVM) probes were used in the development of several challenging crystallization processes. Application of the process knowledge afforded by these technologies, combined with the principles of Quality by Design, resulted in excellent purity control throughout the four-step process. A single, 5-min, MSfriendly method capable of separating over 30 components was developed using a combination of chromatography modeling software, sub-2 µm column technology, and higher-pressure LC equipment. The method was used across all four processing steps, greatly facilitating impurity tracking, and reducing assay time and solvent use by 85% and 93%, respectively.
A new synthesis of a key indazolecontaining building block for the MET kinase inhibitor merestinib was designed and demonstrated. Crucial to the successful construction of the challenging indazole is an S N Ar reaction, which forges the heterocyclic ring. Continuous processing was applied to two of the five steps: nitration of a benzaldehyde and high-temperature hydrolysis of an aniline to phenol. Compared to a highly developed historical route, the new route shows clear benefits in terms of product quality and potentially manufacturability and robustness.
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