Fixed Bed Continuous Hydrogenations in Trickle Flow Mode: A Pharmaceutical Industry Perspective

Abstract

Since the 1930s, fixed bed reactors (FBR) have been operated for continuous hydrogenation reactions in the petrochemical/fine chemical industries, with publications each year detailing engineering principles, scientific breakthroughs, equipment design and setup, from these industries. Only in the last two decades, FBR have started to be utilized in the pharmaceutical industry as a result of sustainability commitment and growing demand of complex and specialized drugs. Most of the engineering knowledge is transferable across industries; however, there are differentiators inherent to each industry, with the pharmaceutical industry having its own unique challenges. One of the main differentiators between industries is the reactor scale and, consequently, reactor catalyst requirements. Petrochemicals or fine chemicals operate on a large industrial scale, with up to 72 m high reactors, with an internal diameter on the order of 5 m (China Petroleum & Chemical Corporation), and require large volumes of catalysts because of the high product demand for thousands of tonnes per year, while for the pharmaceutical industry, a smaller scale reactor is required for product demand in the thousands of kilograms per year range. It is the reactor size that defines catalyst specifications, such as particle size and geometry. Many transformations have emerged from academic and medicinal chemistry groups utilizing the ThalesNano H-Cube; however, there are relatively few reported processes that have been scaled within the pharmaceutical industry. This Perspective outlines a review of continuous flow hydrogenation technologies; focusing on the trickle bed reactor (TBR) and the respective process operation and effect of process variables on reaction rate requirements for the pharmaceutical industry; it also reflects on transformation examples using TBR across the pharmaceutical industry.

Dynamic experiments in flow accelerate reaction network definition in a complex hydrogenation using catalytic static mixers

“…25 Bulk chemical hydrogenations are usually carried out using packed-bed reactors, but pharmaceutical and fine chemical companies have been slower to take up this efficient processing method. 25 In order to encourage this move, alternative continuous flow solutions have been presented, such as reactors containing catalytic static mixers (CSMs). Here, the catalyst is coated on 3D-printed metal inserts, thus providing a high surface area, good heat transfer and low pressure drop, 26 within a tube-in-shell type reactor.…”

Development of a Horizontal Dynamically Mixed Flow Reactor for Laboratory Scale-Up of Photochemical Wohl–Ziegler Bromination

“…According to the Grotthuss–Draper law, light must be absorbed by a chemical substance for a photochemical reaction to occur; when applied to Figure b in the dark area no reaction occurs, emphasizing why mixing is a key parameter in photochemical transformations. , The work of Sczechowski et al on heterogeneous photocatalysis in a Taylor–Couette (Taylor vortex) reactor and the more recent work from Lee et al on the large-scale Taylor–Couette (Taylor vortex) reactor with a predicted productivity of up to 7.45 kg/day was of interest to us. , The mixing that occurs within Taylor–Couette reactors (or Taylor vortex reactors) has been well-characterized via computational fluid dynamics (CFD) modeling; Reynolds numbers and flow structures (flow regimes) for Taylor–Couette reactors are discussed by Grossmann et al , Taylor–Couette flow reactors have a rotating inner smooth or channelled cylinder inside a cylindrical outer to form an annular gap . By varying the rotating cylinder speed, flow rate, and rotating cylinder design, different flow regimes can be achieved . It has also been documented that using a Taylor–Couette-type flow with photochemistry works well due to the increased mass transfer throughout the system. ,,, …”

Utilizing Ni-Catalyzed Cross-Coupling as a Reversed Strategy for Homogeneous Deprotection of Benzyl Ethers in Batch and Flow

“…Continuous hydrogenolysis of benzyl groups can be performed using a packed bed reactor (PBR). 2 This triphasic transformation incorporates a homogeneous substrate stream that reacts with H 2 as it is passed over a catalyst bed (e.g., Pd/ C). High conversions and yields are typically observed with these transformations (Scheme 1A).…”

“…High conversions and yields are typically observed with these transformations (Scheme A) . The downside to operating these PBR hydrogenation systems is the fact that catalyst activity can depreciate over time due to sequestration of catalyst sites from impurities or catalyst leaching. , With significant catalyst deactivation, the process can be limited to a semicontinuous fashion, as the reactor would need to be shut down and depressurized to change out the catalyst bed. A single-phase debenzylation of alcohols capable of being performed in a plug flow reactor (PFR) would offer an alternative continuous method in cases where catalyst deactivation occurs or handling of H 2 gas is restricted.…”