Reactor design and selection for effective continuous manufacturing of pharmaceuticals

Abstract

Pharmaceutical production remains one of the last industries that predominantly uses batch processes, which are inefficient and can cause drug shortages due to the long lead times or quality defects. Consequently, pharmaceutical companies are transitioning away from outdated batch lines, in large part motivated by the many advantages of continuous manufacturing (e.g., low cost, quality assurance, shortened lead time). As chemical reactions are fundamental to any drug production process, the selection of reactor and its design are critical to enhanced performance such as improved selectivity and yield. In this article, relevant theories, and models, as well as their required input data are summarized to assist the reader in these tasks, focusing on continuous reactions. Selected examples that describe the application of plug flow reactors (PFRs) and continuous-stirred tank reactors (CSTRs)-in-series within the pharmaceutical industry are provided. Process analytical technologies (PATs), which are important tools that provide real-time in-line continuous monitoring of reactions, are recommended to be considered during the reactor design process (e.g., port design for the PAT probe). Finally, other important points, such as density change caused by thermal expansion or solid precipitation, clogging/fouling, and scaling-up, are discussed.

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

“…Tubular reactors, also known as plug flow reactors (PFR), plug flow tubular reactors (PFTR) are simple, low-cost continuous tube reactors that are designed to facilitate single-pass (homogeneous catalysis) conversion at high pressure despite being fabricated out of basic tubing or piping. ,− In this reaction system, pre-prepared feed solutions of both catalyst and reagents are connected to feed lines and pumped into the system. The two feeds meet at a mixing point (often a simple “T” connector), while a gaseous reagent can be introduced at a mixing T further along the system prior to the tubular reactor’s inlet. , Once conversion has taken place, the reaction mixture passes through a liquid/gas separator and is collected for workup. , An advantage of tubular reactors is that, unlike in fixed bed reactors, the catalyst used during the transformation is unlikely to degrade over the course of the single pass through the reactor .…”

“…Continuous stirred tank reactors, also known as CSTRs, are the type of flow reactor most similar to batch processing vessels (have a head space). , In a CSTR hydrogenation system, a catalyst solution or slurry can be charged into the agitated reactor via a feed line before the reagent feed and hydrogen feed are added into the CSTR . During operation, the CSTR will run for the desired residence time before emptying and refilling simultaneously for the next cycle, longer residence time can be achieved by using multiple CSTR (i.e., CSTR cascade). , A benefit of CSTR use is that the reagent feed and catalyst are not required to be homogeneous solutions unlike in packed bed reactors where clogging could be an issue, provided that the desired product is soluble.…”

A continuous-flow protocol for photoredox-catalyzed multicomponent Petasis reaction

“…In the last few decades, a constant positive evaluation of the merits of continuous-flow chemistry compared to batch has led to a significant increase in synthetic strategies and reactions developed in microreactors ( Hartman et al., 2011 ; Baumann et al., 2020 ; De Risi et al., 2020 ; Hu, 2021 ). One of the benefits of continuous-flow technology is the possibility to run reactions in micro-diameter reactors, with consequent better heat and mass transport phenomena which can be translated into faster reaction times ( Plutschack et al., 2017 ).…”

Commercial-Scale Visible Light Trifluoromethylation of 2-Chlorothiophenol Using CF3I Gas

“…To overcome each of these challenges, a fiber-coupled laser was substituted as the light source with a continuous stirred tank reactor (CSTR) as the flow reactor. 44 Using this setup, the reaction could be actively and controllably cooled using a jacketed CSTR reactor and a chiller in place of the indirect temperature control of the LED−PFR. While we have previously explored the laser CSTR as a means of delivering higher intensity light to a smaller reactor footprint, in this case, the main advantage of using a fiber-coupled laser was the segregation of the heat associated with light generation from the reactor itself, allowing for greater temperature control.…”

“…Our efforts in scaling the PFR highlighted several challenges that had been foreseen for scaling this type of reactor, namely, controlling reactor temperature in the presence of high-intensity irradiation from LEDs. To overcome each of these challenges, a fiber-coupled laser was substituted as the light source with a continuous stirred tank reactor (CSTR) as the flow reactor . Using this setup, the reaction could be actively and controllably cooled using a jacketed CSTR reactor and a chiller in place of the indirect temperature control of the LED–PFR.…”