(369b) Recrystallization Development for Small Molecule API (Active Pharmaceutical Ingredient) Islatravir | AIChE

(369b) Recrystallization Development for Small Molecule API (Active Pharmaceutical Ingredient) Islatravir


Bade, R. - Presenter, Merck & Co., Inc.
Varsolona, R., Merck & Co., Inc.
Stueber, D., Merck & Co., Inc.
Sirk, K., Merck
Heltzel, J., George Washington University
Koynov, A., Merck
Margelefsky, E., Merck & Co., Inc.
Islatravir is a nucleoside reverse transcriptase inhibitor small molecule API (active pharmaceutical ingredient) targeted for HIV PrEP (pre-exposure prophylaxis). Islatravir has multiple crystal forms and a complex phase diagram. This talk will focus on the conversion from the monohydrate to an anhydrous form. To produce anhydrous API, we have designed a slurry conversion process, during which the less stable monohydrate form dissolves and a more stable anhydrous form crystallizes simultaneously. The solution composition also comes into play, as the process requires operating within a specific window of water-activity for effective form conversion. The slurry conversion process is also designed to proceed in a controlled manner to reduce crystallization of another kinetically favored phase. In addition, Merck has recently published a novel biocatalytic synthetic scheme for the synthesis of Islatravir*. This presentation will discuss differences in anhydrous crystallization performance (morphology, particle size, and milling performance) when starting with API from a traditional chemical synthetic route vs. the novel biocatalytic route. In this talk, we discuss the factors we can manipulate to design the most robust process, ultimately producing anhydrous API with consistent properties across various batches.

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