Two Approaches to Effective Particle Size and Impurity Control - METTLER TOLEDO

Two Approaches to Effective Particle Size and Impurity Control

Crystal Engineering Islatravir

Islatravir (MK-8591), a highly potent nucleoside reverse transcriptase translocation inhibitor, is being developed by Merck to stem the spread of global HIV infections. Following a nine-enzyme in-vitro synthesis from 2-ethynylglycerol without intermediate isolation, a crude active pharmaceutical ingredient with high levels of biological and chemical impurities must be purified through recrystallization. As a potent compound with efficacy at sub-milligram doses, islatravir requires a robust crystallization process for consistent particle size to meet content uniformity requirements in a tablet.

Two robust crystallization methods were developed and scaled-up that both delivered a controlled particle size distribution (PSD) and improved impurity profile. The first process implements jet-milled seed to control PSD, an effective yet costly approach that also posed industrial hygiene concerns. Due to elucidating the crystallization mechanism, dry milling was able to be avoided in the second process with a novel shear-induced nucleation and thermal annealing crystallization (SINTAX). The SINTAX process promotes secondary nucleation via wet milling and simultaneous antisolvent charge, followed by a thermal annealing phase to dissolve fines and improve purity. In this presentation, we compare the impacts of the two crystallization processes on impurity rejection, PSD, and processability.

Join the hundreds of researchers who already viewed the presentation.

Scott Quirie - Merck & Co, Inc.
Scott Quirie - Merck & Co, Inc.