A robust, green, and sustainable manufacturing process has been developed for the synthesis of gefapixant citrate, a P2X3 receptor antagonist that is under investigation for the treatment of refractory and unexplained chronic cough. The newly developed commercial process features low process mass intensity (PMI), short synthetic sequence, high overall yield, minimal environmental impact, and significantly reduced API costs. The key innovations are the implementation of a highly efficient two-step methoxyphenol synthesis, an innovative pyrimidine synthesis in flow, a simplified sulfonamide synthesis, and a novel salt metathesis approach to consistently deliver the correct active pharmaceutical ingredient (API) salt form in high purity.
The development of a sustainable commercial salt formation process for gefapixant citrate (MK-7264), an investigational new P2X3 antagonist for the treatment of chronic cough, is described. Due to the low solubility of the gefapixant free base, the first-generation process for citrate salt formation was a slurry-to-slurry process with poor quality control, wherein impurities were not well rejected and unreacted free base often persisted in the citrate produced. The development of a controlled crystallization from a homogeneous solution, which overcame these deficiencies, was complicated by solubility constraints and a daunting solid form landscape. Herein, we report a novel solution to this problem where the free base is transiently converted to a highly soluble glycolate salt enabling complete dissolution, from which direct crystallization of the final citrate salt occurs in a high yield through salt metathesis. Robust crystallization control was ensured by conducting a comprehensive polymorph screen on the glycolate salt and demonstrating its metastability compared to the desired citrate salt. In addition, process-relevant solvates of the citrate salt were discovered and derisked via a thorough understanding of their stability regions. With this information, a secondgeneration process salt formation with robust crystalline form and purity control was achieved, utilizing a salt metathesis co-feed process that greatly reduces the amount of solvent required, the overall manufacturing time, and the energy consumption compared to the first-generation conditions.
To address time lost due to inadequate assessment and understanding of solids suspension issues, empirical studies were conducted at pilot scale using a calcium carbonate and de-ionized water (DIW) system. Three tools were used and evaluated to understand suspension status: (1) turbidity meter response, (2) off-line sample analysis, and (3) difference between baffle and bottom temperatures. The data from these studies demonstrated that the most effective tool that also required the least effort was the difference between baffle and bottom temperatures. A standardized experimental procedure was developed and can be used to gain empirical suspension data at scale for any desired solid-liquid system. This procedure involved performing temperature adjustments in the vessel and observing the associated baffle/bottom temperature changes for varying agitator speeds.
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.
Severe operational challenges were experienced during the delumping (via comilling) of a shear-sensitive active pharmaceutical ingredient (API) during a pilot plant campaign. During the in-line comilling operation from the dryer, the API melted and blinded the screen, which compromised the equipment and called the batch fitness for formulation into question. These challenges instigated the investigation of comilling parameters and API physical properties, and their respective effects on delumping performance as well as the final API attributes. Comil impeller speed, impeller type, screen hole size, and screen hole type were studied at both pilot plant and lab scale. The unique properties of the API were also studied in order to understand how this solid differed from others. Because solids with similar physical properties to the API in question are likely to behave in a similar way, the experimental approach described here for comil and solid characterization should be applicable to other projects as well. The optimal comilling conditions for the API were determined and demonstrated robustly at pilot scale.
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