In the pharmaceutical industry, high throughput (HT) technology is well developed and routinely utilized in chemical process development for reaction optimization and isolations via crystallization. However, fewer HT technologies have been employed in the development of workup procedures, bridging optimized reaction and isolations. Frequently, extensive workups involving numerous unit operations are required to remove reaction stream components, such as impurities, solvent, and catalyst, prior to isolation. Herein, we describe a systematic yet flexible approach using designed experimentation, laboratory automation, and parallel experimentation to quickly and efficiently optimize unit operations that are required post reaction to remove reaction stream components (e.g., impurities, metal catalysts, solvent). This novel high throughput extraction (HTEx) platform has shown potential to broadly impact development by faster and more robustly improving process greenness, process mass intensity (PMI), cycle time, and ease of operation.

Deucravacitinib (BMS-986165) is a deuterated small-molecule TYK2 inhibitor developed for the treatment of numerous autoimmune disorders. While the first-generation discovery chemistry route to access deucravacitinib was concise and sufficient to access kilogram quantities of API, impurity control and cost-of-goods concerns necessitated the design of a new route. Once a new route was identified and demonstrated, each step was optimized for yield, purity, robustness, and sustainability. Key accomplishments include (1) the development of a novel cyclocondensation under mild conditions to afford a methylated 1,2,4triazole with excellent regiocontrol, (2) the development of safe, homogeneous conditions to quench POCl 3 following chlorination of a substrate that is sensitive to nucleophilic and basic conditions, (3) the discovery of a robust, scalable "dual-base" palladiumcatalyzed C−N coupling reaction, and (4) mechanistic understanding to inform control strategies for a number of process-related impurities in an API step amidation mediated by EDC. Ultimately, the optimized commercial route was successfully scaled up to afford more than a metric ton of deucravacitinib for clinical and commercial use.

Herein, a population balance model (PBM) for a combined cooling and antisolvent crystallization process for an active pharmaceutical ingredient (API) has been developed and utilized to predict the product particle size distribution (PSD) for two sets of four ∼35 kg scale plant batches, with good agreement to data. The PBM was constructed from lab-scale (∼10 g) crystallization runs using seed and product PSD measurements along with concentration measurements of the API during batch desupersaturation experiments. The PBM was then used to predict the product PSD for two sets of four plant batches, run using different reactors equipped with different agitator types operated at different agitation rates. Analysis of the crystallization kinetics reveals that secondary nucleation due to attrition has a strong influence on the PSD in the crystallization process of the API, and thus mixing conditions (agitator type, agitator speed, pumping, and power numbers) have a strong effect on PSD. The model provides a more robust particle size control strategy than design of experiment (DOE) studies alone by incorporating fundamental crystallization kinetics, with data from a small set of lab experiments in lieu of extensive DOE studies. This firstprinciple-based approach was useful for enhancing the robustness of the technical transfer process by accounting for impacts on product PSD stemming from process scale-up and parameter changes.