(601d) Islatravir Penultimate Step Crystallization: Purification of an API in the Presence of High Protein Loading from an Enzymatic Cascade
The primary challenge in the purification development has been on enzyme/protein removal. The presence of high levels of protein tends to make filtrations very slow, so extractive work-ups are often preferable, but the relatively low solubility of the API in most organic solvents was a formidable obstacle to this approach. Several extractive work-ups were developed but each posed stability concerns.
Additionally, enzyme immobilization was pursued for the enzymes with the highest loadings in the reaction, which improved downstream processing but added a significant cost and supply-chain complexity.
In the final reaction, the API crystallizes from the reaction mixture, and even wth several enzymes removed via immobilization, filtration was still very challenging. Filtration was optimized by adding filter aid (diatomaceous earth), reducing shear in the reaction, adding seed crystals to the reaction, and agitating the batch intermittently during filtration. Optimizing the filtration step to isolate the crude API made it possible to produce quality API without the need to develop an extractive work-up or use immobilized enzymes.
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