(594e) A Miniature CSTR Platform for Continuous Processing of Multiphase Systems

Continuous manufacturing has emerged as a powerful tool for producing fine chemicals (e.g. active pharmaceutical ingredients (APIs)) over the past decade. However, numerous important reactions in pharmaceutical industry involve multiphase interactions, which create challenges for flow chemistry to gain a wider acceptance. For example, the presence of stoichiometric amount of solids as reagents, by-products, or products leads to the issue of blocking a flow reactor, and the problem is more severe for the milli-scale or micro-scale flow systems. Besides, the mass transfer resistance at the phase boundaries sometimes becomes the rate-limiting step. Considering current widely used tubular reactors, only providing limited interfacial interactions imposed by the laminar flow pattern, a more universal and versatile reactor design is desired for handling solids in flow, generating well-controlled mixing performance, and at the same time, offer compatibility to withstand harsh chemical environment.

Here, we present a new miniaturized continuously stirred-tank reactor (CSTR) for continuous processing of multiphase systems. The design, with the feature of plug-and-play, takes efficient mass and heat transfer, chemical compatibility, and ease to fabricate and clean into account. Single-phase residence time distribution (RTD) measurements of the CSTR unit reveal nearly ideal CSTR mixing. It also has the capability to tune the RTD by connecting several units in series to achieve approximate plug flow reactor (PFR) RTD, which gives the flexibility to optimize the selectivity based on the reaction kinetics.

Two versions of miniature CSTRs were developed for: (i) solid handling in flow, and (ii) high-performance liquid-liquid mixing.

Solid handling CSTR: employing the non-stick polytetrafluoroethylene (PTFE) as the reactor body material with minimized inter-unit connection enables the CSTR to continuously handle high-concentrated slurries for hours without significant signs of clogging. Two solid-forming reactions, (i) glyoxal reacting with cyclohexylamine to form N,N′-dicyclohexylethylenediimine, and (ii) sulfonylation of 2-octanol with methanesulfonyl chloride, demonstrate its practical usefulness as a powerful for flow chemistry field.

High-performance liquid-liquid CSTR: incorporating the magnetic-coupling as the driving force to provide external agitation inside the confined reactor space gives the possibility to generate extraordinary two-phase mixing performance without losing the capability to seal the reactor. We demonstrate the reactor with a comparable liquid-liquid mass transfer coefficient to Corning Advance-flow Reactor, which is the state-of-the-art among commercial reactors. More importantly, it gets around the problem of coupling of flowrate and mixing, and is capable to accommodate reaction kinetics from seconds to hours. Phase transfer catalyzed reactions were demonstrated in this newly designed CSTR, with the corresponding kinetic model developed for Makosza phase-transfer mechanism. In addition, the success of carrying out biphasic Suzuki-Miyaura reactions further validates its suitability for the pharmaceutical applications.