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Kilogram-scale prexasertib monolactate monohydrate synthesis under continuous-flow CGMP conditions
Ist Teil von
Science (American Association for the Advancement of Science), 2017-06, Vol.356 (6343), p.1144-1150
Ort / Verlag
United States: American Association for the Advancement of Science
Erscheinungsjahr
2017
Quelle
Science Online
Beschreibungen/Notizen
Advances in drug potency and tailored therapeutics are promoting pharmaceutical manufacturing to transition from a traditional batch paradigm to more flexible continuous processing. Here we report the development of a multistep continuous-flow CGMP (current good manufacturing practices) process that produced 24 kilograms of prexasertib monolactate monohydrate suitable for use in human clinical trials. Eight continuous unit operations were conducted to produce the target at roughly 3 kilograms per day using small continuous reactors, extractors, evaporators, crystallizers, and filters in laboratory fume hoods. Success was enabled by advances in chemistry, engineering, analytical science, process modeling, and equipment design. Substantial technical and business drivers were identified, which merited the continuous process. The continuous process afforded improved performance and safety relative to batch processes and also improved containment of a highly potent compound.