(467d) Multi Scale Flowsheet Simulation for the Purification and Processing of Active Pharmaceutical Ingredients | AIChE

(467d) Multi Scale Flowsheet Simulation for the Purification and Processing of Active Pharmaceutical Ingredients


Chaudhury, A., Rutgers, The State University of New Jersey
John, J., Rutgers, The State University of New Jersey

The quality of the final pharmaceutical products depends on the raw material (API) properties and purity. So an efficient production, separation and purification process through which the desired API properties and purity can be achieved is highly desired. Continuous mode of operation makes it possible to follow state of the art techniques to satisfy the final product requirements [1].  Continuous manufacturing leads to improved QbD (Quality by design) and also result into better implementation of the PAT (Process analytical technology) tools for real time monitoring and control of product quality attributes. Therefore transition from batch to continuous mode of production has been one of the prime objectives in the pharmaceutical industries. However, continuous manufacturing and separation of APIs is still a challenging task because of different level of complexities involved because the downstream separation and purification processes involves complex phenomena and are still least understood. It is important to understand each and every unit operation which is a part of the continuous process so that the desired operational level can be achieved. On one hand the complex particle interactions involved in the operations need to be understood and on another hand the flow behavior during operation is also important to analyze.  Therefore, an efficient hybrid mathematical model, so called integrated continuous flow sheet model coupled with CFD model is highly desired.

In the work reported here, an integrated flow sheet model for continuous separation, purification and processing of APIs has been developed. The flow sheet is based on the first principle models of each unit operations involved in separation and purification steps of API (crystallization, filtration, drying, mixing). A flow sheet is designed by integrating all these unit operations.  As a result an actual plant operation can be approximately represented with the help of a robust flow sheet model [2]. The developed flow sheet model has several applications such as to understand, design and optimize the process and its control system that will regulate the process and also to identify and fix the bottlenecks in design and control objectives. The flow sheet, coupled with CFD for crystallization (Computational fluid dynamics) and DEM (discrete element models)  for mixing, provides a multi- scale framework which can incorporate information from particle level to the unit-operation level.

The objective of this work is to highlight the scope of integrated flow sheet modeling coupled with CFD and to demonstrate the developed multi-scale framework for downstream processing of active pharmaceutical ingredient (API). Downstream processing of API in pharmaceutical industries includes formation of API crystals during the crystallization operation, filtration of the API crystals from the mother liquor and drying of the crystals. Crystals of different size are formed during crystallization of API. There is further size change during drying when the particles shrink due to moisture removal. Hence a population balance model has been formulated in order to represent each the unit operations with size changes. A flow sheet has been developed by integrating each of these unit operations. The population balance model has been built using gPROMS (Process System Enterprise) which is a robust and fast equation oriented software allowing both steady state and dynamic simulation runs. A CFD model can be coupled with the population balance model in order to account for the mixing of the fluid phase in an agitated crystallizer and agitated dryer.


[1] A. Gorsek, P. Glavic, Design of batch versus continuous processes: part 1: single-purpose equipment, Chemical Engineering Research and Design 75 (1997) 709-717

[2] F. Boukouvala, V. Niotis, R. Ramachandran, F. Muzzio, M.G. Ierapetritou, An integrated approach for dynamic flowsheet modeling and sensitivity analysis of a continuous tablet manufacturing process: an integrated approach, Computers and Chemical Engineering, doi:10.1016/j.compchemeng.2012.02.015