Investigating the isolation performance of a novel continuous filtration unit for pharmaceutical process development and manufacturing: a case study using paracetamol and related impurities

Sara Ottoboni, Muhid Shahid, Christopher Robert Steven, Elizabeth Meehan, Alastair Barton, Paul Firth, Richard Sutherland, Andy Mitchell, Furqan Tahir, Chris John Price

Research output: Contribution to conferenceProceeding

1 Citation (Scopus)


There is a significant gap in the availability of equipment with appropriate capacity for laboratory process development, pilot plant and small manufacturing scale using dead end continuous filtration and drying. To advance small-scale pharmaceutical isolation forward from traditional batch Nutsche filtration to continuous processing, a continuous filter dryer prototype unit (CFD20) was developed in collaboration with Alconbury Weston Ltd (AWL) as part of the REMEDIES programme. The technical challenges and the key performance indicators for such a unit were identified and the prototype solution was evaluated by comparing the functionality and performance of the CFD20 unit against manual best practice executed using a Biotage manual filtration unit. Two different paracetamol grades, micronized and granular, were selected as model materials and Patent V blue dye as a soluble impurity. The knowledge gathered during this work was used to facilitate the development of a commercial unit (CFD25).
In order to test the utility of the CFD25 as a process development tool a design of experiments approach was used to develop a procedure to reduce agglomeration during isolation and to enhance impurity removal. The effect of input slurry properties, such as; solid loading, particle size distribution and crystallization solvent were investigated to determine their impact on the filtration and washing performance and the characteristics of the dry isolated product. Two different grades of API were used, a typical crystalline product, and micronized API. The role of washing was explored by analysing the effect of different crystallization and wash solvents and the quantity of wash solvent used to remove paracetamol related impurities such as acetanilide and metacetamol. Product crystal suspensions were prepared using three potential crystallization solvents; ethanol, isopropanol and isoamyl alcohol. Three different wash solvents were evaluated. n-heptane and isopropyl acetate were selected based on their miscibility with the primary crystallization solvents to facilitate diffusional and dilution washing mechanisms; isopropyl acetate and n-heptane exhibit relatively high and very low paracetamol solubility respectively. The third wash solvent n-dodecane was selected as an immiscible wash solvent to exemplify displacement washing in the absence of miscibility. In each case, the wash strategy was designed to minimise the nucleation of new crystals during washing. An inappropriate washing strategy can lead to precipitation of both API and impurities dissolved in the mother liquors, which may modify the final PSD or reduce the purity of the final isolated material.
Filter cake properties were determined using the on-board machine vision system in the CFD which was used to halt filtration at dryland and to record filtration rate data. The filter cake and filtrate were both analysed using HPLC to quantify the purification achieved. The mechanical properties of the isolated product were evaluated; the extent of agglomeration, the agglomerate particle size distribution and the agglomerate strength were all measured. Proton nuclear magnetic spectroscopy (1H NMR) was used to determine the residual solvent in the dried filter cake.
The AWL CFD25 is designed to accelerate the early development of continuous API isolation processes by using a modest quantity of slurry per measurement allowing experimental design to be conducted early in the development cycle. A good level of purification was achieved using wash volume equivalent to 4 cake void volumes. It was demonstrated that low boiling aliphatic hydrocarbons are particularly effective to reduce the extent of agglomeration and to form softer agglomerates.
Original languageEnglish
Number of pages1
Publication statusPublished - 25 Apr 2018
EventFiltCon 2018 - Prior Lake, MN, USA, United States
Duration: 23 Apr 201825 Apr 2018


ConferenceFiltCon 2018
Country/TerritoryUnited States


  • continuous filtration
  • washing
  • drying
  • agglomeration
  • paracetamol
  • paracetamol related impurities
  • isolation strategy
  • optimisation
  • case study


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