Digital design of filtration and washing of active pharmaceutical ingredients via mechanistic modelling

Ottoboni, Sara and Brown, Cameron J. and Mehta, Bhavik and Jimeno, Guillermo and Mitchell, Niall A. and Sefcik, Jan and Price, Chris J. (2022) Digital design of filtration and washing of active pharmaceutical ingredients via mechanistic modelling. Organic Process Research and Development, 26 (12). pp. 3236-3253. ISSN 1083-6160 (

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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 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 modelling 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 digital design of filtration and washing processes.