(601e) Development of a Crystallization Process for the Final Step of the Biocatalytic Synthesis of Islatravir

Merck recently reported a biocatalytic cascade for the manufacture of Islatravir, a potent HIV reverse transcriptase translocation inhibitor [1]. The API step of the synthesis requires removing protein and other impurities accumulated throughout the synthesis. Also, the low dose of the drug requires API particle size control in the final step to mitigate content uniformity concerns in the tablet. This industrial case study will provide an overview of the development of a pure step that meets purity and particle size targets. The presentation will highlight the development of a novel crystallization process to meet the desired particle size distribution while maintaining a rapid filtration rate of the product crystals. The scale-up crystallization performance and impurity rejection of the process will also be compared to a more ‘traditional’ seeded crystallization using jet milled seed. The development of the process was motivated by the desire to eliminate the cost and industrial hygiene liabilities associated with dry milling API as seed.

[1] Huffman et al. “Design of an in vitro biocatalytic cascade for the manufacture of islatravir.” Science, 2019, 366 (6470), 1255-1259.