Development and Demonstration of a Co-feed Process to Address Form and Physical Attribute Control of the Gefapixant (MK-7264) Citrate Active Pharmaceutical Ingredient

The final chemical transformation and isolation in the synthesis of an active pharmaceutical ingredient (API), referred to as the Pure Step, is often chemically simple but scientifically, operationally, and strategically the most challenging. Pure Step development is critical because it is used to determine and support the critical quality attributes (CQAs) for the API, which will have lasting impacts on both the drug substance and drug product processes. This paper will detail specific challenges for the gefapixant (MK-7264) API, which is isolated as a citrate salt crystallized out of methanol and isopropanol. This citrate salt is then formulated via direct compression to make the final dosage form for the patient. This salt crystallization is particularly challenging due to (1) the propensity of the citrate salt crystal to form solvates, (2) the particle size control requirements, and (3) the variability in crude API purity during development (crude API is the starting material for the Pure Step). The project team had to simultaneously execute targeted, rapid process development to support pilot plant API batches, which supplied clinical trials, tech transfer the process to the manufacturing site overseas, and provide requisite experimental data to support characterization and mechanistic understanding. This work has required technical excellence, streamlined collaboration, and flawless communication across the integrated drug substance/drug product space. The comprehensive process development work resulted in the development of a thermodynamically controlled Pure Step crystallization that yields quality gefapixant API for successful and robust drug product processing.