Modeling of pharmaceutical filtration and continuous integrated crystallization-filtration processes

Abstract

As continuous manufacturing is evolving in the pharmaceutical industry, continuous filtration has emerged as a bottleneck for connecting the crystallization of the active pharmaceutical ingredient with the formulation of the final drug product. This work aims the modeling of filtration to improve the understanding of the process, to support the development of continuous filtration methodologies, and to aid the integration of crystallization and filtration. The presented model utilizes the generalized form of Darcy’s law together with the calculation of the cake porosity and specific cake resistance based on the full crystal size distribution (CSD) of the slurry, without the need for experimental filtration data. The model is applied the first time for the dynamic simulation of an automated batch- type continuous filtration, which is also integrated with a population balance model of crystallization. The effect of the slurry properties (solid concentration, CSD) and the crystallization and filtration process parameters (crystallization temperature, flow rates, filter pressure difference, carousel rotation time) on the specific cake resistance, filtration time and residual moisture content are determined. It is concluded that continuous filtration facilitates the filtration of slurries with bad filterability through the modification of the rotation time and provides an opportunity to control the filtration when connected to a continuous crystallization. The simulation results show good agreement with real integrated continuous crystallization and filtration experiments of acetylsalicylic acid. The presented methodology could be used for both batch Nutsche filtration and continuous filtration to predict filterability and for optimization, risk analysis and control purposes.