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Development of an automated multi-stage continuous reactive crystallization system with in-line PATs for high viscosity process

Authors

Introduction

Pharmaceutical synthesis remains one of the last industrial processes to use “batch” or non-continuous approaches.1 Conversely, other industries, such as petrochemicals, automobiles, electronics, and food, have moved forward with automated and continuous operations. Pharmaceutical companies generally manufacture the active pharmaceutical ingredient (API) at one company plant, and formulate the API with excipients into the final drug product at a separate plant. It is a fragmented process with a long lead-time and a large plant footprint. This time–space inefficiency has led to an increased interest in integrated continuous manufacturing (ICM) of APIs and drug products as a seamless end-to-end process. Advantages of continuous manufacturing include:

  1. Flexibility,
  2. Speeding up the supply chain,
  3. Agility and reduced scale-up efforts,
  4. Real-time quality assurance and better engineered systems,
  5. Recentralized and individualized manufacturing,
  6. Reduced footprint and investment costs, and
  7. Societal benefits

Continuous manufacturing processes of pharmaceuticals can include the following steps: reaction, crystallization, filtration, drying, and hot melt extrusion (HME).

Abstract

An automated multi-stage continuous reaction system with in-line PATs for a high viscosity reactive crystallization process was developed in the present study. Data acquisition (DAQ) hardware and Labview software were used as the local control system. A “forward-backward” burst pumping strategy was developed to smoothly transfer the highly viscous hot slurry from one vessel to the next. In addition, a comparative analysis between a plug flow reactor (PFR) and continuous stirred-tank reactors (CSTRs) in series revealed that to achieve the same conversion, the latter would require more volume than the former, but less than a single CSTR. For a second-order reaction, the value of the Damköhler number necessary to achieve conversion of 90.0% in a single CSTR is 90. Thus, it is reasonable to approximate a PFR using CSTRs in series to obtain a high yield with a smaller reaction volume (compared with a single CSTR). As the probes could not be positioned in the hot slurry due to fouling issues, in-line focused beam reflectance measurement (FBRM) and React IR were used to monitor the crystal size and reactant concentration in the vessel containing the cold slurry. E-factors of batch and continuous processes were also compared and the continuous reaction could obtain a lower E-factor because less waste was generated.

Abstract Image

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