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.
The large-scale manufacture of complex
synthetic peptides is challenging
due to many factors such as manufacturing risk (including failed product
specifications) as well as processes that are often low in both yield
and overall purity. To overcome these liabilities, a hybrid solid-phase
peptide synthesis/liquid-phase peptide synthesis (SPPS/LPPS) approach
was developed for the synthesis of tirzepatide. Continuous manufacturing
and real-time analytical monitoring ensured the production of high-quality
material, while nanofiltration provided intermediate purification
without difficult precipitations. Implementation of the strategy worked
very well, resulting in a robust process with high yields and purity.
A mechanistic approach was undertaken to understand the oxygen sensitivity of a Pd-catalyzed amination reaction used in the synthesis of an active pharmaceutical ingredient. FlowNMR and dissolved oxygen probes were used as process analytical technology alongside kinetic and unit operation models to better characterize the oxidative deactivation pathways of the catalyst. Interplay between ligand excess, oxygen inertion, and additional degassing due to reflux were all found to contribute to reaction rate variability. This mechanistic approach allowed for appreciation and clear communication of the risks, development of protocols to mitigate those risks, and successful scale-up under rapid development timelines.
The synthesis of 5-bromo-thiophene-2-sulfonic acid 2,4-dichlorobenzoylamide sodium salt on multikilogram scale is described. The initial clinical supplies were made using carbonyl diimidazole to converge the two fragments. A more efficient acid chloride process has been developed, which also provides better control of impurities and color throughout the synthesis.
The synthesis of
a MET kinase inhibitor in an overall yield of
22% was achieved over eight steps starting with 3-hydroxybenzaldehyde,
an improvement from the initial 12-step process with a 5.4% yield.
Highlights of the process chemistry design and development are a Cu-catalyzed
cyclization to form an important N1-methylindazole
ring, a selective nitro reduction in the presence of an aryl bromide,
a late-stage Suzuki cross-coupling, and a base-promoted Boc deprotection
to form the desired drug candidate.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.