Flowsheet optimization of an integrated continuous purification-processing pharmaceutical manufacturing operation

Maitraye Sen, Amanda Rogers, Ravendra Singh, Anwesha Chaudhury, Joyce John, Marianthi G. Ierapetritou, Rohit Ramachandran

Research output: Contribution to journalArticlepeer-review

39 Scopus citations


In this work, a continuous API purification process has been optimized using an integrated flowsheet model. The simulation is dynamic in nature and includes an API purification step (crystallization), followed by filtration, drying and mixing of the API with an excipient. For the first time, this study demonstrates the use of a reduced order model (ROM) within the mixing unit for prediction of particle velocities that is coupled with a population balance model (PBM) of the mixer to quantify macroscopic properties. The main objective is to optimize the integrated flowsheet model such that there is an overall improvement in process operation. The optimum cooling schedule during crystallization has been obtained. The optimum values of filter pressure gradient, drying gas temperature and mixer RPM (speed) have also been determined. It is seen that the optimized operating conditions give a narrower CSD of the API crystals and lower RSD (Relative standard deviation) of the final mixed product, compared to nonoptimal operating condition. The developed model can be used as an effective tool in control and optimization and can have future implementation in design of a Process Analytical Technology (PAT) system which can lead to improved operation of the manufacturing process.

Original languageEnglish (US)
Pages (from-to)56-66
Number of pages11
JournalChemical Engineering Science
StatePublished - Oct 1 2013

All Science Journal Classification (ASJC) codes

  • Chemical Engineering(all)
  • Chemistry(all)
  • Industrial and Manufacturing Engineering


  • Continuous manufacturing
  • Crystallization
  • Flowsheet optimization
  • Population balance model
  • Powder mixing


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