(542e) Crystallization Engineering for the Robust Manufacturing of Islatravir Using SINTAX (shear-induced nucleation and thermal annealing crystallization)

Islatravir (MK-8591) is a potent nucleoside reverse transcriptase translocation inhibitor in development for HIV treatment and prevention. We have developed a robust crystallization method that ensures the active pharmaceutical ingredient (API) meets the required purity and physical property attributes to enable sub-milligram doses and multiple formulation types. Our crystallization takes a crude API, containing high levels of biologic and chemical impurities, and produces an API with high purity for drug substance quality and consistent particle size for content uniformity and improved manufacturing.

Herein, we highlight the development and scale-up of a shear-induced nucleation and thermal annealing crystallization (SINTAX) that delivers islatravir with a controlled particle size distribution and impurity profile¹. We emphasize lessons learned by applying SINTAX at the lab, pilot, and commercial scales. Across manufacturing scales, we demonstrate the robustness of SINTAX and the importance of solubility models and process analytical technologies (PAT). Altogether, we show the importance of crystallization engineering to control impurity rejection, particle characteristics, and processability for the development of a life-changing drug.

References:

1. Sirota, E., Kwok, T., et al. "Crystallization Process Development for the Final Step of the Biocatalytic Synthesis of Islatravir: Comprehensive Crystal Engineering for a Low-Dose Drug." Organic Process Research & Development 25.2 (2021): 308-317.