Small-molecule APIs dominate pharmaceutical manufacturing, so where may future innovation reside? The scientific literature abounds with novel approaches to a given synthesis or refinements to existing syntheses as a means to improve product yield, process conditions, enantioselectivity, or production economics. These efforts are an integral part of process development and commercial manufacturing and will continue to be so. But what may be the game-changer in small-molecule manufacturing? As we consider the possibilities, continuous-flow technology through micreactors as an alternative to traditional batch manufacturing may be one possibility.
Continuous flow technology
Continuous-flow technology involves the continuous introduction of a stream of chemical reactants into a flow or microreactor to yield a desired reaction product on a continuous basis (1). Continuous-flow technology may offer potential advantages compared with traditional batch manufacturing of pharmaceuticals, such as greater optimization and control of the process, an improved safety and environmental profile for a given process, and a reduced manufacturing footprint compared with batch-reactor systems (1).In general,microstructured devices with small internal volumes and high surface-to-volume ratios offer transport capabilities for rapid mixing, enhanced heat transfer for good temperature control, and intensified mass transfer (2). Microstructured devices operate in a continuous-flow environment, which can provide controlled process conditions, high flow rates, and high mass throughput. Continuous operations also may allow for bulk-chemistry processes to have high production capacities. Fluid dynamics determine the characteristics of continuous-flow equipment, such as pressure loss, heat-transfer characteristics, residence time, and mixing time (2, 3).
The factory of tomorrow
Reflecting growing interest in microreactor technology for fine-chemical manufacturing, Lonza reported earlier this year investment in what it terms the “Factory of Tomorrow,” at its facility in Visp, Switzerland. The facility will offer production of multiton intermediates and/or APIs based on continuous-flow processing. Lonza currently operates assets that can produce several kilograms to several tons of small-molecule APIs using microreactors. The new facility will provide an integrated solution where all common unit operations in flow can be streamlined in a flexible fashion using microreactors (FlowPlate, Lonza). The facility was slated to be operational in June 2012.
The new unit will enable the integration of complete flow processes in addition to microreactors, according to company information. It will be able to integrate a range of flow reactors, such as continuous stirrer tank reactors or ultrasounds and streamline flow processes, including work-up unit operations, such as liquid–liquid extraction, distillation (wiped-film, thin film). Higher pressure applications will be enabled as well by allowing gas–liquid reactions, such as ozone and HCN chemistries. The technology can be used for chemical reactions under severe and extreme conditions, such as very high temperatures or cryogenic conditions.
Marrying engineering and chemistry
Effectively applying continuous-flow technology involves a multidisciplinary approach of chemistry and engineering. As an example, researchers at the Massachusetts Institute of Technology (MIT) 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 Klaus 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 (3–5).
1. J. Hamby, “API Synthesis, Formulation Development, and Manufacturing” supp. Pharm. Technol. 34 (9), s18–19 (2010).
2. N. Korman et al., “API Synthesis, Formulation Development, and Manufacturing” supp. Pharm. Technol. 34 (9), s32–s36 (2010).
3. P. Van Arnum, Pharm. Technol. 35 (8), 52–56 (2011).
4. T. Noel et al., “Suzuki–Miyaura Cross-Coupling Reactions in Flow: Multistep Synthesis Enabled by a Microfluidic Extraction,” Agnew. Chem. Int. Ed. online, DOI: 10.1002/anie.201101480, May 17, 2011.
5. S.R. Ritter, Chem. & Eng. News 89 (23), 39 (2011).