3D Printed Reactors for Synthesis of Active Pharmaceutical Ingredients in Continuous Flow

Abstract

Advances in flow chemistry to produce active pharmaceutical ingredients (APIs) require performing reactions in tailor-made equipment as complexity of the planned setups increases. To react quickly and with low costs to these demanding reactions, additive manufacturing, also known as 3D printing, is a preferred way for the production of customized reactors. This work presents three examples of 3D printed reactors and their application for the synthesis of API precursors in continuous flow. The first case deals with an aerobic oxidation of Grignard reagents to the corresponding phenols by molecular oxygen. Here, a design concept was utilized; various stainless steel reactors were tested, and their performances were evaluated in continuous flow. Next, another stainless steel reactor was applied for achieving fast mixing in a cascade, leading to a valsartan precursor. The third and final case employed a continuous stirred tank reactor (CSTR) made of a UV-curable resin. It was used for the first step of a multiphase enzymatic decarboxylation followed by a Heck cross-coupling reaction, leading to resveratrol derivatives.

3D-printing design for continuous flow catalysis

“…Synthesis of valsartan, a non-peptide angiotensin II receptor blocker, was accomplished following a tandem strategy based on N-acylation reaction, Pd-catalyzed Suzuki-Miyaura cross-coupling, and ester hydrolysis was performed in coil reactors. Particularly in the last case, the process involved the enzymatic decarboxylation of phenolic acids followed by heterogeneously catalyzed Heck cross-coupling reaction, demonstrating the versatility of 3D printing for catalytic applications, including photo-, electro-, and biomimetic catalysis, as will be also exemplified in the following sections [62].…”

3D printed ceramics as solid supports for enzyme immobilization: an automated DoE approach for applications in continuous flow

“…The outlets of the pumps were then connected to a static mixer, in order to provide a feed stream with uniform concentration before it reaches the column inlet. As static mixer, a 3D printed stainless steel microfluidic device was used, which was designed in our group and characterized in a previous work [ 58 ]. This chosen device was the so-called AP04 with an internal diameter of 0.6 mm, into which the solvent and the substrate solution were mixed according to a split-and-recombine principle.…”

“…This chosen device was the so-called AP04 with an internal diameter of 0.6 mm, into which the solvent and the substrate solution were mixed according to a split-and-recombine principle. The AP04 was chosen as static mixer since it was proved in a previous publication [ 58 ] that it provides reasonably good degrees of mixing while remaining a compact device. The feed was then pumped into one of the columns, each connected to a six-way-valve (Knauer Azura VU 4.1), which dictates the column into which the feed is pumped to.…”

Photobiocatalysis in Continuous Flow

“…Since for open-source projects all files, parts and codes are available, these systems are easily adaptable to the process at hand. Moreover, due to the increase in knowledge about additive manufacturing, tailor-made photoreactors can be realized via 3D printing also for specific purposes (Capel et al, 2018;Maier et al, 2020). By combining 3D printed parts with low-cost microcontrollers and electronics, it is possible to realize customized and integrated processes, where some selected process parameters (e.g., concentration, temperature and light intensity) can be controlled and investigated (Valotta et al, 2021).…”