Research ArticlesVolume 13, Spring 2019

Designing an Industrially Scalable, Flow-Based Synthesis for the Production of Nilotinib: Chemical Process Modeling & Economic Analysis

Nilotinib (Tasigna) is a drug used to treat chronic myelogenous leukemia (CML), a disease which currently affects over 100,000 people in the U.S. The drug is manufactured by Novartis and has been one of its most profitable, bringing in a total revenue of well over $2 billion USD in 2016. Novartis’ s patent on T asigna is set to expire in 2023 and cheaper, generic versions of the drug will soon be in great demand. An assessment of Novartis’ s existing patent on the synthesis of T asigna indicates many drawbacks in the current process. Namely, the Novartis synthesis requires multiple days of reaction, nearly a dozen steps, multiple solvent switching processes, and gives very low yields. On the other hand, work published by Buchwald and coworkers has shown an efficient method of synthesizing nilotinib in fewer than four steps, in less than 24 hours, and at >85% yields. Unfortunately, the Buchwald reaction has only ever been applied in a laboratory setting and has never been scaled to an industrial level. Thus, it was the goal of this investigation to develop an industrially scaled, flow-based synthesis of the Buchwald synthesis of nilotinib. For this investigation, our team assumed the role of a generic pharmaceutical company with a hypothetical goal of producing 15% of the U.S. market share of nilotinib (1150 kg of nilotinib/year). Utilizing chemical reaction modeling software, ChemCAD, a chemical process for the large scale Buchwald synthesis of nilotinib was successfully designed at the 1150 kg production capacity of the active pharmaceutical ingredient of nilotinib per year. Economic analysis demonstrated the fiscal viability of this process with estimated gross revenue of >$250 million USD/year even with a predicted 60% drop in generic drug price factored in. This, we envision, would serve as an important improvement in the efficiency of industrial level synthesis of a life-saving cancer drug.