Batch vs. Continuous

Early-stage process development to introduce new molecules is often performed in a batch mode. This process steps typically include synthesis, separation, and purification. However, when the development team explores the commercial viability of the new process technology, the decision of batch vs. continuous operating mode is critical. Depending on the process technologies and materials, many factors and potential tradeoffs need to be considered when identifying the most optimal operation mode. Examples include process safety, complexity, product form & quality, production volume, manufacturing cost, investment & physical footprint, production time, location, waste generation, sustainability, and commercialization timeline. This session will cover how the differences in the benefits & risks for these aspects impact the batch vs. continuous process decision and resulting commercial viability.

Session Chairs:

• Omid Ebrahimpour, DuPont
• Stephen Tieri, DuPont

Schedule:

Abstracts:

Pending finalization - Please check back soon for updates

Going with the Flow: Performance Drivers for Pharmaceutical Development and How Flow Chemistry Fits into the Mix

Eric R. Sacia, AbbVie

Flow processes offer differentiated advantages in their ability to carry out challenging chemical reactions safer and often faster, with smaller footprint, and with more consistent quality.  However, much of pharmaceutical development is still performed in batch processing due to constraints of existing infrastructure, convention, perceived regulatory restrictions, and availability of adequate Engineering resources to support the scale-up challenges.  In this talk, two case studies will be provided to discuss advantages and opportunities for pharmaceutical processes executed in flow vs. batch.

In the first case study, the emerging use of visible light as a “reagent” for photochemically-driven organic reactions will be discussed.  Photochemical methodologies enable complex organic molecules to be synthesized with catalysts that can facilitate single-electron transfer from the catalyst’s excited state.  Such reactions are often difficult to selectively enable through more conventional two-electron processes.  However, to develop and scale-up such syntheses, appropriate chemical reactors must be designed and validated to enable demonstration and commercial production at manufacturing sites.  For this purpose, flow reactors can provide an attractive advantage to improve reactor productivity, photon flux, heat transport, and mass transport.  For this reason, a laser-driven continuously-stirred tank reactor (CSTR) has been successfully implemented for developing and scaling photocatalytic chemistries.

In the second case study, the role of reactor design on selective hydrogenation chemistry will be discussed.  Reactor design and operating parameters (e.g. – pressure, temperature, gas-to-liquid ratio, catalyst loading, and residence time) may have a profound impact on substrate enantioselectivity and reactor robustness.  While hydrogenations in flow are ubiquitous in the petroleum industry, their adoption in the pharmaceutical industry has not been nearly as widespread.  For this reason, we will describe how fit-for-purpose modeling may be used to rapidly identify optimal conditions and configurations for flow hydrogenation development and why they can be advantaged over batch operation.

Finally, a brief perspective will be provided on barriers and scale-up challenges for processes in the pharmaceutical industry.  This review will cover the constraints and areas of growth for future processing capabilities in batch and flow within the sector.

 

From High Throughput Screening to Continuous Process Development: Synthesis of 1,6-Hexanediol by Hydrodeoxygenation of Biomass-Derived Feedstocks

Sourav K. Sengupta, DuPont

Since the beginning of the 21st century, the chemical industry has been making many novel and ingenious innovations to design cost-advantaged, inherently safe, and sustainable processes based on renewably sourced feedstocks for the production of fuels, chemicals, and advanced materials. However, there is still a persistent public perception that the chemical industry is not doing enough to develop safe and sustainable chemistry. As a matter of fact, a large number of scientists, environmental scholars, business leaders, and governmental policymakers believe that chemical industry must do more to develop sustainable processes to save our planet from the dire consequences of climate change. During the last three decades, DuPont has been in the forefront of developing sustainable products and processes. One such endeavor was to develop a cost-competitive process for the synthesis of 1,6hexanediol from renewable feedstocks. Several potential feedstocks have been investigated with the main intermediates being 1,2,6-hexanetriol (1,2,6-HT) and tetrahydropyran-2-methanol (THP2M) as shown in Figure 1. 

Figure 1: Reactions highlighting the main intermediates for converting biomass-derived feedstocks to

renewable 1,2-hexanediol 

Multimetallic catalysts have been shown to be valuable for a variety of industrially-practiced reactions,

including biomass valorization. We have explored the activity, selectivity, and life of supported metalmetal oxide catalyst combinations using high throughput screening and continuous tickle bed reactors for the  hydrodeoxygenation of biomass-derived feedstocks [1-5].



The development work started with the synthesis and screening of plethora of supported metal and

metal-oxide catalyst systems (Figure 2). The initial proof of concept (PoC) was performed in small highthroughput batch reactors (milligram quantity of catalysts in powder form). After completing PoC, the process was transferred from batch reactors to continuous reactors, which comprised of high-throughput trickle-bed test units (gram catalyst scale, in powder form, with 16 reactor tubes in parallel) to closely match the operating conditions of a commercial continuous hydrodeoxygenation process. The first two steps comprised of screening several hundred catalysts under a broad range of operating conditions to determine the activity, selectivity, and stability of the catalysts. Performance targets were set based on the initial results and techno-economic evaluation. In the next step, several lead catalyst candidates were identified and subsequently scaled-up to shapes (extrudates and pellets) and sizes (e.g., 1/16” and 1/8”) similar to that of standard commercial catalysts. During this evaluation process, a few grams of the selected catalysts were further optimized by extending the range of operating conditions. In the final stage of the development work, the amount of catalyst was increased into hundred-gram scale using a semiworks-scale test rig. The latter had a lower degree of parallelization but a high degree of flexibility for each catalyst system. The catalyst systems were operated independently in their preferred reaction conditions and over a longer period with industrially relevant feedstock to assess long-term catalyst stability. Larger quantities of the effluent streams were collected for more detailed product analytics and separation and purification workstreams. The results obtained from the reactor scale-up study were used to further refine the techno-economic analysis and were used as an input for designing the pilot plant. 

Figure 2: Development cycle for producing 1,6-HD from C6 polyols.

The catalyst scale-up in this example involved shell impregnation of commercial supports. The product analysis involved detailed GC-MS and GC-FID/TCD analyses of the gas- and liquid-phase products. The testing included batch and continuous high throughput screening and flexible semiworks-scale reactor system. The performance of the catalysts, with special reference to Pt-WOx/TiO2, the lead catalyst candidate, for the hydrodeoxygenation of 1,2-HT and THP2M and the significance of the batch and continuous reactor systems for the synthesis of 1,6-HD will be discussed in the presentation. 

References

1. Allgeier, A. M., Carlson; T. R., Corbin, D. R., De Silva, W. I. N., Menning, C. A., Ritter, J. C., and

Sengupta, S. K., Production of alpha, omega-diols US 9,670,118 (2017)  

2. Allgeier, A. M., Carlson; T. R., Corbin, D. R., De Silva, W. I. N., Korovessi, E., Menning, C. A., Ritter,

J. C., Rosenfeld; H. D. and Sengupta, S. K., Production of alpha, omega-diols US 9,181,157 (2015)  

3. Stauffer, C. S., Sengupta, S. K., Ritter, J. C., Menning, C. A., Korovessi, E., De Silva, W. I. N., Allgeier,

A. M., Process for Preparing 1,6-Hexanediol, US 8,865,940 (2014)

4. Stauffer, C. S., Sengupta, S. K., Ritter, J. C., Menning, C. A., Korovessi, E., De Silva, W. I. N.,

Allgeier, A. M., Process for Preparing 1,6-Hexanediol, US 8,865,940 (2014)

5. Stephens, K. J., Allgeier, A. M., Bell, A. L., Carlson, T. R., Chen, Y., Douglas, J. T., Howe, L. A.,

Menning, C. A., Neuenswander, S. A., Sengupta, S. K., Thapa, and Ritter, J. C. P. S. A Mechanistic

Study of Polyol Hydrodeoxygenation over a Bifunctional Pt-WOX/TiO2 Catalyst, ACS Catal. 10,

12996−13007 (2020)