Advancing Flow Chemistry in API Manufacturing - Pharmaceutical Technology

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Advancing Flow Chemistry in API Manufacturing
Continuous flow chemistry offers potential for greater control, improved safety and environmental profiles, and efficient chemical transformations.


Pharmaceutical Technology
Volume 37, Issue 4, pp. 78-82

Technology advances

Scientists at Eli Lilly recently reported on reactions in a continuous mode in plug-flow tube reactors (PFRs) to enable chemistry that would be difficult to perform by means of batch processing. Specifically, they developed two different continuous flow approaches for producing a 1H-4-substituted imidazole intermediate. In a first-generation approach, rapid optimization and scale-up of a cyclization reaction was shown in a PFR under GMP conditions to produce 29 kg of protected product. This material was further processed in batch equipment to deliver the di-HCl salt. This approach showed the development of chemistry in research-scale PFRs and speed to material delivery through linear scale-up to a pilot-scale PFR under GMP conditions (5). In a second-generation effort, a more efficient synthetic route was developed, and PFRs with automated sampling, dilution, and analytical analysis allowed for reaction optimization of a cyclization reaction and thermal removal of a Boc protecting group. This work culminated in 1-kg demonstration runs in a 0.22 L-PFR for both continuous steps and showed the potential of commercialization from a laboratory hood footprint (1–2 metric tons/year), according to the researchers (5).

In another project, researchers at Eli Lilly reported on a fully continuous process, which involved an asymmetric hydrogenation reaction operating at 70 bar hydrogen, aqueous extraction, and crystallization that was designed, developed and demonstrated at pilot scale. Production of 144 kg of product was made in laboratory fume hoods and a laboratory hydrogenation bunker over two continuous campaigns (6). Maximum continuous flow vessel size in the laboratory hoods was 22-L glassware, and maximum PFR size in the bunker was 73 L (6). The researchers reported that main safety advantages of running the hydrogenation reaction continuous rather than batch were that the flow reactor was smaller for the same throughput, and the tubular hydrogenation reactor ran 95% liquid-filled at steady state. The amount of hydrogen in the reactor at any one time, therefore, was less than that of batch. Additionally, a two-stage mixed suspension–mixed product removal cascade was used for continuous crystallization (6). The researchers reported that impurity rejection by continuous crystallization was better than by batch because scalable residence time and steady-state supersaturation allowed for repeatable control of enantiomer rejection in a kinetic environment (6). The researchers reported that a fully continuous wet-end process running in a laboratory infrastructure achieved the same weekly throughput that would be expected from traditional batch processing in a plant module with 400-L vessels (6).

Researchers at the Massachusetts Institute of Technology (MIT) recently reported on the application of compact crystallization, filtration, and drying for producing APIs. Specifically, they developed a combined crystallization and hybrid filtration-drying-dissolution apparatus for a compact manufacturing platform. Crystallization experiments using a conventional stirred tank and a newly designed scraped surface crystalliser showed advantages in terms of crystallization rates, yields, and the ease of automation (7).

The scraped surface crystallizer used an anchor impeller to create a closed clearance between the crystalliser wall and impeller. The researchers reported that the design prevented crystallization on the wall, generated large crystals to facilitate filtration, and improved draining and washing for automation. The hybrid device intensified three unit operations (filtration, drying, and dissolution/suspension) into a single unit. Intensifying these unit operations potentially reduces the time and material lost due to pumping and reduces contact between the API, the environment and operators. Postcrystallization operations were operated step-wise using the custom hybrid device that delivered satisfactory results for each operation. Fluoxetine HCl was dried in less than 20 minutes, with 99% yield after dissolution in a liquid excipient (7).

Effectively applying continuous-flow technology involves a multidisciplinary approach of chemistry and engineering. As an example, other MIT researchers reported on the development of a Suzuki–Miyaura cross-coupling reaction in a continuous-flow microreactor system. Suzuki coupling is a palladium-catalyzed coupling between organoboron compounds and organohalides and is an important reaction in organic chemistry in general and for pharmaceutical compounds specifically. The researchers developed a continuous-flow Suzuki–Miyaura cross-coupling reaction that started from phenols and produced various biaryls in good yield using a microfluidic-extraction operation and a packed-bed reactor. The project used a multidisciplinary approach with the research on microreactor technology developed by a team led by Klavs F. Jensen, department head, Warren K. Lewis professor of chemical engineering, and professor of materials science and engineering at MIT. The organic synthesis portion of the project was developed by a group led by Stephen Buchwald, Camille Dreyfus professor of chemistry at MIT (1, 4, 8, 9).


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