Development of a Green and Sustainable Manufacturing Process for Gefapixant Citrate (MK-7264). Part 5: Completion of the API Free Base via a Direct Chlorosulfonylation Process

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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.

Section: Introductionmentioning

confidence: 99%

Development of a Green and Sustainable Manufacturing Process for Gefapixant Citrate (MK-7264). Part 6: Development of an Improved Commercial Salt Formation Process

Maloney

Zhang

Mohan

et al. 2020

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“…This challenge was addressed using a combination of one factor at a time (OFAT) experiments and impurity spiking experiments. As previously mentioned, process development for synthetic chemistry steps were occurring in parallel, so close collaboration with the free base step team was required for efficient evaluation and experimentation . For several key impurities, authentic samples were spiked to generate even higher levels than what was specified for the free base to investigate the purging capabilities of the co-feed process.…”

Section: Development Of the Co-feed Processmentioning

confidence: 99%

“…As previously mentioned, process development for synthetic chemistry steps were occurring in parallel, so close collaboration with the free base step team was required for efficient evaluation and experimentation. 11 For several key impurities, authentic samples were spiked to generate even higher levels than what was specified for the free base to investigate the purging capabilities of the co-feed process. This lab development demonstrated that the new cofeed process could achieve equivalent or better API purity compared to the batch process, as shown in Table 1.…”

Section: ■ Project Backgroundmentioning

confidence: 99%

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

Mohan

DiBenedetto

Alwedi

et al. 2021

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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.

“…At 25 °C, the acetonitrile solvate was more stable than the anhydrous form at >15 vol % acetonitrile (vs water). 52 The compound is crystallized via the addition of citric acid to a basic solution of compound B to afford the neutral compound B in ∼80/20 v/v water/acetonitrile. To demonstrate the impact of the crystal form on impurity rejection, two crystallizations were performed with the same feed stream and ending at the same solvent composition.…”

Section: Industrial Case Study 2: Impurity Forming Solid Solution Wit...mentioning

confidence: 99%

Prevalence of Impurity Retention Mechanisms in Pharmaceutical Crystallizations

Nordström

Sirota

Hartmanshenn

et al. 2023

The rejection of process impurities from crystallizing products is an essential step for the purification of pharmaceutical drugs and for the isolation of active pharmaceutical ingredients with the right crystal quality attributes. While several impurity incorporation mechanisms have been reported in the literature, the frequency of those mechanisms in actual industrial processes is largely unknown. This work presents the outcome of a joint investigation by crystallization scientists from two pharmaceutical companies and an academic institution, on the prevalence of impurity retention mechanisms in cooling and antisolvent crystallizations. A total of 52 product-impurity pairs have been explored in detail using the so-called Solubility-Limited Impurity Purge (SLIP) test as the diagnostic tool to identify the underlying impurity retention mechanism of already crystallized materials with challenging impurities. The results show that formation of solid solutions is the most common mechanism, where the impurity and product are partially miscible in the solid state. In 73% of cases, only one solid solution phase was obtained in which the impurity became incorporated into the crystal lattice of the product (α phase). In 6% of the examples, two solid solution phases were obtained, where the second solid phase (β phase) comprised predominantly the impurity and the product was the minor component. The remaining impurity retention mechanisms (21%) are related to solid-state immiscible impurities that precipitated from solution resulting in a physical mixture between the product and the impurity. The reasons for the results are discussed through a comprehensive analysis of theoretical reported retention mechanisms, which includes physical constraints for the scale-up of isolation processes, thermodynamic assessments using ternary phase diagrams, and restrictions in the context of current pharmaceutical syntheses of small organic molecules. Three industrial case studies are presented that exemplify how knowledge of the retention mechanisms can be used to delineate appropriate strategies for process design and to effectively purge these impurities during crystallization or washing.