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.
A scalable and efficient synthesis of hydroxyindanone 3, a key intermediate for belzutifan (MK-6482), is described. Mechanistic studies revealed the sensitivity of the reduction reaction toward the CO2 byproduct. Special effort was required to design a scale-insensitive process for the removal of CO2 with active nitrogen headspace sweeping, supported by process modeling and verification with process analytical technology data. Automated sampling facilitated data-rich experimentation via kinetic profiling, culminating in enhanced understanding and further robustness-based optimization for the reduction reaction. Herein we report the development of a one-pot through-process with direct isolation of 3 in high yield (>90%) and purity (>99 LCAP, >99 ee) at commercial scales. The newly developed process ensures process robustness and improves cycle times and process mass intensity.
Our company has developed a robust and scalable process to synthesize an amino alcohol tosylate salt, a penultimate intermediate in the synthesis of nemtabrutinib. A key reaction in this synthetic sequence is a reductive acetal ring opening using boron trifluoride diethyl etherate as a Lewis acid and triethylsilane as the reducing agent. Detailed mechanistic inquisition revealed that in the presence of sulfolane, boron trifluoride is reduced by triethylsilane to generate diborane as the active reductant. Diborane poses many process safety hazards; it is highly reactive, flammable, and acutely toxic. The reaction headspace was studied using infrared spectroscopy and gas chromatography, while the reaction stream was studied using heat flow and adiabatic calorimetry to ensure safe scale-up of the process. Process understanding demonstrated that containing diborane within the reactor was essential to control key impurities. Extensive development efforts were directed to design a process that could safely sequester the hazardous gas. Herein, we describe the process safety analysis, the optimization, and the scale-up of the reduction reaction and the isolation, producing two batches of the amino alcohol tosylate salt with high purity at a pilot scale.
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