Digital Design of Filtration and Washing of Active Pharmaceutical Ingredients via Mechanistic Modeling

Abstract

To facilitate integrated end-to-end pharmaceutical manufacturing using digital design, a model capable of transferring material property information between operations to predict product attributes in integrated purification processes has been developed. The focus of the work reported here combines filtration and washing operations used in active pharmaceutical ingredient (API) purification and isolation to predict isolation performance without the need of extensive experimental work. A fixed Carman–Kozeny filtration model is integrated with several washing mechanisms (displacement, dilution, and axial dispersion). Two limiting cases are considered: case 1 where there is no change in the solid phase during isolation (no particle dissolution and/or growth), and case 2 where the liquid and solid phases are equilibrated over the course of isolation. In reality, all actual manufacturing conditions would be bracketed by these two limiting cases, so consideration of these two scenarios provides rigorous theoretical bounds for assessing isolation performance. This modeling approach aims to facilitate the selection of most appropriate models suitable for different isolation scenarios, without the requirement to use overly complex models for straightforward isolation processes. Mefenamic acid and paracetamol were selected as representative model compounds to assess a range of isolation scenarios. In each case, the objective of the models was to identify the purity of the product reached with a fixed wash ratio and minimize the changes to the crystalline particle attributes that occur during the isolation process. This was undertaken with the aim of identifying suitable criteria for the selection of appropriate filtration and washing models corresponding to relevant processing conditions, and ultimately developing guidelines for the digital design of filtration and washing processes.

Integrated Filtration and Washing Modeling: Optimization of Impurity Rejection for Filtration and Washing of Active Pharmaceutical Ingredients

“…The integrated filtration and washing model were developed in 3 stages: Filtration is modeled as a batch process, using a pressure filter model described elsewhere . Filtration stops at dryland, leaving the cake pore saturated with mother liquor.…”

“…The integrated filtration and washing model were developed in 3 stages: Filtration is modeled as a batch process, using a pressure filter model described elsewhere. 36 Filtration stops at dryland, leaving the cake pore saturated with mother liquor. Dryland refers to a filtration stopping point where there is theoretically no mother liquor left on the surface of the cake (i.e., the free liquid height is zero) Filtration and washing are modeled using a pressure filter model, where washing stages are done after filtration to dryland.…”

“…Dead-end filtration used in this work has been described elsewhere. 36 The filtering process was simulated using the gPROMS FormulatedProducts v2.3.1 pressure filtration model, where the Carman–Kozeny theory was used to evaluate the resistance of the cake. The filtration process was modeled considering the initial conditions as reported in Table 6 .…”

“…Filtration is modeled as a batch process, using a pressure filter model described elsewhere. 36 Filtration stops at dryland, leaving the cake pore saturated with mother liquor. Dryland refers to a filtration stopping point where there is theoretically no mother liquor left on the surface of the cake (i.e., the free liquid height is zero) 2.…”

“…The equations used for the displacement and for the diffusion-dispersion washing models were described in Section 3.2.3 by Ottoboni et al 36 2.4.3. Model Validation, Qualitative Optimization, and Design Space Exploration.…”