Advancing Flow Chemistry in API Manufacturing

imagewerks/GETTY IMAGESContinuous-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, 2). Continuous-flow technology offers potential advantages compared with traditional batch manufacturing of pharmaceuticals, such as greater optimization and control of the process, improved safety and environmental profiles for a given process, and a reduced manufacturingfootprint (1,2). Pharmaceutical companies, fine-chemical producers, and academia are pursuing continuous-flow chemistry in the production of APIs and related relevant reactions with several interesting developments in this field.

Evaluating the technology

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 (1, 3). 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 (1-4). The high surface-area-to-volume ratio comparative to a batch reactor enables better temperature control overall, including for exothermic reactions, which improves processing conditions. Scale-up issues may be minimized due to maintaining improved mixing and heat transfer.

Recent activity

These benefits are attracting investment and R&D in continuous-flow chemistry. In February 2013, DSM Pharmaceutical Products signed an agreement with Chemtrix, a supplier of flow-chemistry equipment and services, for providing equipment, development, and manufacturing services to the pharmaceutical industry. Chemtrix specializes in ready-to-use laboratory and kilo-scale microreactors as well as reactor and process design for industrial reactors. DSM provides drug-synthesis route development, scale-up, and implementation of continuous-flow processes for manufacturing. DSM has FDA approval for using microreactors for making a pharmaceutical product at commercial scale under cGMP at its facility in Linz, Austria, where its dedicated commercial-scale installation is located. Initially, the DSM–Chemtrix collaboration will offer an industrial flow process-development package for customized scalable flow-chemistry solutions. The package covers all phases of process design, scanning chemistries, chemistry development, route scouting, equipment design, and scale-up for fully continuous or integrated processes.

Reflecting growing interest in microreactor technology for fine-chemical manufacturing, Lonza invested in what it terms the “Factory of Tomorrow,” at its facility in Visp, Switzerland. The investment, made in 2012, enables production of multitons of intermediates and/or APIs based on continuous-flow processing. Lonza operates assets that can produce several kilograms to several tons of small-molecule APIs using microreactors, and the new unit in Visp adds an integrated solution where all common unit operations in flow can be streamlined in a flexible fashion using microreactors (FlowPlate, Lonza) (1). This new unit integrates a range of flow reactors, such as continuous stirrer-tank reactors or ultrasounds and streamlines flow processes, including work-up unit operations, such as liquid–liquid extraction and distillation (wiped-film, thin film). Higher pressure applications are 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 high temperatures or cryogenic conditions (1).

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 was73 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).

Other developments

Scientists at LyraChem, based in Newcastle-upon-Tyne, United Kingdom, and Newcastle University reported on intensified azeotropic distillation as an approach for optimizing direct amidation (10). The direct synthesis of amides from the corresponding carboxylic acids and amines was shown to operate under varying degrees of mixed kinetic and mass-transfer rate control when water was removed by azeotropic distillation (10). A systematic approach was developed to quantify the contribution of boil-up rate to conversion rate and decouple the physical rates from the chemistry. Intensive boiling was used to improve the removal of water during azeotropic distillation and enhance conversion. The researchers reported that some acylations previously thought to be difficult or impossible could be achieved in the absence of coupling agents under green conditions. A cascade of continuous stirred-tank flow reactors operating under intensified conditions was assessed for scale-up of direct amidation reactions and compared to a production-scale batch reactor. The researchers reported that the use of the continuous stirred-tank flow reactors operating under intensified conditions could provide the necessary high rates of heat transfer and, therefore, offer advantages over a conventional batch reactor system (10).

Asymmetric synthesis is an important area of research for producing single enantiomer drugs. Researchers in the Department of Chemistry, School of Science at the University of Tokyo, recently reported on the use of continuous-flow chemistry with chiral heterogeneous catalysts in asymmetric carbon–carbon bond formation (11). They developed and applied a chiral calcium catalyst based on calcium chloride with a chiral ligand to the asymmetric 1,4-addition of 1,3-dicarbonyl compounds to nitroalkenes as a model system (11). The researchers sought to improve the low catalyst turnover number (TON) of asymmetriccarbon–carbon bond-forming issues (12). To address product inhibition, the calcium catalyst was applied to continuous flow with a chiral heterogeneous catalyst. The continuous-flow system, using a newly synthesised, polymer-supported Pybox, was successfully used, and the catalyst TON was improved 25-fold compared with those of the previous Ca(OR)2 catalysts (11).

Researchers at the Department of Synthetic and Biological Chemistry in the Graduate School of Engineering, Kyoto University Nishikyo-ku, in Kyoto, Japan applied a flash-chemistry approach using flow microreactors to produce a highly reactive palladium catalyst with a tri-tert-butylphosphine (tBu3P) ligand for a Suzuki–Miyaura coupling (12, 13). The flash chemistry enabled the use of highly reactive unstable species as a catalysts for chemical synthesis. Fast micromixing of a solution of [Pd(OAc)2] and that of tBu3P in an 1:1 mole ratio gave a solution of a highly reactive unstable species, which was transferred to a vessel by using a flow microreactor, in which Suzuki–Miyaura coupling was conducted (13). The coupling reactions were completed in 5 minutes at room temperature, thereby preventing deboronation of the used aryl and heteroarylboronic acids (12).

In another study, researchers from the Institute of Science and Technology in Ikoma, Japan, and the School of Pharmacy and Molecular Sciences at James Cook University in Townsville, Australia reported on the diastereoselective [2+2] photocycloaddition of a chiral cyclohexenone with ethylene in a continuous flow microcapillary reactor (14). The researchers reported that the microcapillary reactors have higher conversions and selectivity than the batch system even after shorter irradiation times due to better temperature control, light penetration and generation of gas–liquid slug flow with improved mass transfer in the microreactor (14).

In another development, researchers at the Institute of Organic Chemistry at Aachen University in Germany reported on the asymmetric organocatalytic hydrogenation of benzoxazines, quinolines, quinoxalines and 3H-indoles in continuous-flow microreactors using Fourier transform infrared (FTIR) spectroscopy in-line analysis (15). Reaction monitoring was achieved by using an in-line ReactIR flow cell, which allowed for optimization of the reaction parameters. The researchers reported that the reductions proceeded well, and the desired products were isolated in high yields and with good enantioselectivities (15).

References

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2. J. Hamby, “API Synthesis, Formulation Development, and Manufacturing” supplement to Pharm. Technol. 34, s18–19 (2010).

3. N. Korman et al., “API Synthesis, Formulation Development, and Manufacturing” supplement to Pharm. Technol. 34 , s32–s36 (2010).

4. P. Van Arnum, Pharm. Technol. 35 (8), 52–56 (2011).

5. S.A. May et al., Org. Process Res. Dev. 16 (5), 982-1002 (2012).

6. M.D. Johnson et al., Org. Process Res. Dev. 16 (5), 1017-1038 (2012).

7. S.Y. Wong et al., Org. Process Res. Dev. , online, DOI: 10.1021/op400011s, Mar.17, 2013.

8. T. Noel et al., Agnew. Chem. Int. Ed. online, DOI: 10.1002/anie.201101480, 17 May 2011.

9. S.R. Ritter, Chem. & Eng. News 89 (23), 39 (2011).

10. C. Crosjean et al., Org. Process Res. Dev. 16 (5), 781-787 (2012).

11. T. Tsubugo, Y. Yamashita, and S. Kobayashi et al., Chem. Eur. J. 18 (43), 13624-13628 (2012).

12. T. N. Glasnov, J. Flow Chem. 3 (4), 135-141 (2012).

13. A. Nagaki et al., Chem. Eur. J. 18 (38), 11871-11875 (2012).

14. K. Terao et al., J. Flow Chem. 2 (3), 73-76 (2012).

15.M. Rueping, T. Bootwicha, and E. Sugiono, Beilstein J. Org. Chem. 8, 300-307 (2012).