Crystallization Process Development for the Final Step of the Biocatalytic Synthesis of Islatravir: Comprehensive Crystal Engineering for a Low-Dose Drug

Islatravir (MK-8591), a highly potent nucleoside reverse transcriptase translocation inhibitor, is being developed to stem the spread of global HIV infections. Following a nine-enzyme in vitro synthesis of islatravir from 2-ethynylglycerol without intermediate isolation, a crude active pharmaceutical ingredient with high levels of biological and chemical impurities must be purified through recrystallization. With efficacy at sub-milligram doses, islatravir requires a robust crystallization method for consistent particle size to meet content uniformity requirements in a tablet. Herein, we outline the development of two robust crystallization methods that deliver purified islatravir with a controlled particle size distribution (PSD) and impurity profile. We present the development and scale-up of a crystallization using a jet-milled seed to control particle size. We also present the development and scale-up of a novel shear-induced nucleation and thermal annealing crystallization (SINTAX) that avoids the use of dry milling. The impacts of the two crystallization processes on impurity rejection, PSD, and processability are highlighted. Thermal annealing of a slurry after secondary nucleation in the SINTAX process is shown to provide substantial purification benefits.