Process Development, Manufacture, and Understanding of the Atropisomerism and Polymorphism of Verinurad

Abstract

The manufacturing route toward verinurad, an amphoteric, class II atropisomer that readily forms solvates, has proven to be highly complex. This previously required the isolation of intermediates with challenging physical properties and the application of cryogenic processes. New processes were designed and optimized, enabling the manufacture of 113 kg of verinurad in its desired polymorphic form. An interdisciplinary approach involving the synthesis, high-throughput experimentation, analytical chemistry, crystallization science, in silico modeling, and engineering was employed. Kinetic measurement of enantiomerically enriched verinurad salts confirmed that racemization occurred within the clearance time frame, thus mitigating safety concerns associated with inherent axial chirality in verinurad.

Recent Expedition in Pd‐ and Rh‐Catalyzed C(Ar)−B Bond Formations and Their Applications in Modern Organic Syntheses

“…Verinurad, a highly potent selective URAT1 inhibitor for the treatment of chronic kidney disease was manufactured by multi‐steps including borylation of aryl bromides (Scheme 28b) [108] . The ArBpin product was then converted to a DEA boronate ester.…”

“…Verinurad, a highly potent selective URAT1 inhibitor for the treatment of chronic kidney disease was manufactured by multi-steps including borylation of aryl bromides (Scheme 28b). [108] The ArBpin product was then converted to a DEA boronate ester. The reaction protocol was found to be scalable up to 113 kg of Verinurad, with high yield and good purity suitable for clinical use.…”

Approaches to Synthesis and Isolation of Enantiomerically Pure Biologically Active Atropisomers

“…Despite the fact that introducing atropisomerism into drug candidates makes synthesis and isolation challenging and, therefore, adds extra cost for active pharmaceutical ingredient (API) manufacture, there are several FDA approved atropisomeric drugs on the market and under development in the pharmaceutical industry . Notably, AstraZeneca’s marketed drug Verinurad, a highly potent URAT1 inhibitor, is a class 2 atropisomer that is administered as a mixture of atropisomers since its half-life is too short to allow manufacture of the single form . Neurokinin antagonists are other examples of class 2 atropisomeric drug candidates developed internally …”

“…11 Notably, AstraZeneca's marketed drug Verinurad, a highly potent URAT1 inhibitor, is a class 2 atropisomer that is administered as a mixture of atropisomers since its half-life is too short to allow manufacture of the single form. 12 Neurokinin antagonists are other examples of class 2 atropisomeric drug candidates developed internally. 13 In AstraZeneca's program to develop selective, covalent KRAS G12C inhibitors, a series of fused piperazine-quinazoline scaffolds comprising a biaryl atropisomeric axis were identified as potent inhibitors with good biophysical and pharmaceutical properties.…”

Understanding Crystal Structures to Guide Form Selection of Active Pharmaceutical Ingredients: A Case Study of AZD9567

“…In early phase drug development, covering preclinical, phase I and II studies, the constraints from a solid-state perspective are the limited amount of materials available for development and the limited amount of solid-state information for the drug candidates itself. , Nevertheless, the attempts to mitigate solid-state landscapes such as rapid polymorph screens, crystallization screens, and salt/cocrystal screens are conducted as early as possible, − including miniaturization and automation. , One of the outcomes of early solid-state screening work is the availability of crystal structures, determined mostly by single-crystal X-ray diffraction. Single crystals that represent the “pure” polymorphic form will unequivocally provide important information to structural aspects such as polymorphic stability assessments and any potential physicochemical properties that might cause issues during upcoming development. , The usage of crystal structures as an early tool for building solid form understanding and confidence has been shown for some APIs such as meglumine, bufexamac, cediranib maleate, or GW825964X. ,, …”