Continuous reactive crystallization of an API in PFR-CSTR cascade with in-line PATs

Abstract

The continuous reactive crystallization of an active pharmaceutical ingredient (API) in a plug flow reactor (PFR)-continuous stirred tank reactor (CSTR) cascade system with in-line PATs was developed and investigated. Residence...

Reactor design and selection for effective continuous manufacturing of pharmaceuticals

“…ReactIR is a real-time, in situ mid-infrared based system that enables tracking of soluble reactants, intermediates, products and by-products during the reaction process. This provides useful information about initiation, conversion, intermediates and endpoints of a reaction [8,16,[91][92][93]. A ReactIR probe could be located in a batch reactor, a CSTR, or any stage of a CSTRs-in-series, while a ReactIR flow cell can be placed at the exit of a PFR [94].…”

“…FBRM is a probe-based instrument that tracks changing particle size and counts in real-time, and has been widely used in: 1) developing and optimizing crystallization process [95][96][97][98][99], 2) tracking and troubleshooting crystallizer systems [100][101][102][103][104][105], and 3) even monitoring polymorphic forms [103,106]. The FBRM probe could be located in a batch crystallizer, or in CSTRs-in-series systems for reactive crystallization processes [8,16]. For example, Hu et al [8,16]used FBRM in the last stage of CSTRs-in-series to track changing chord length in real time.…”

“…Motivated by the benefits shown in Fig. 1 [6][7][8][9][10], the pharmaceutical industry is transitioning to continuous processes, including end-to-end integrated continuous manufacturing (ICM) approaches [1,6,8,[10][11][12][13][14][15][16][17][18]. A first-of-its-kind research demonstration of an end-to-end ICM line was unveiled by MIT in 2011 [13].…”

“…The model drug was aliskiren hemifumarate, and the throughput of the process was 45 g/h, with a residence time of 47 h. Subsequently, the first commercial-setting end-to-end ICM pilot plant was reported by CONTINUUS Pharmaceuticals in 2019 [12]. The throughput of the process was 4800 tablets per hour, or 40.3 × 10 6 tablets per year, with a total residence time of <30 h. There are examples of continuously manufactured drug products that have been approved in the US (e.g., Orkambi Johnson & Johnson, Verzenio by Eli Lilly), as well as drugs that are under development [12,16,19]. The reaction is one of the necessary steps in the continuous manufacturing of pharmaceuticals.…”

“…Solid lines are experimental RTD profiles and dashed lines are RTD profiles based on a CSTRsin-series model. (Reproduced from Ref [16]. with permission from the Royal Society of Chemistry)…”