(203f) Continuous Solvent Exchange Washing of Pharmaceutical Intermediates

M. Kreimer¹, I. Aigner¹, S. Sacher¹, M. Krumme², T. Mannschott², P. van der Wel³, A. Kaptein³, J.G. Khinast^1,4

¹Research Center Pharmaceutical Engineering (RCPE) GmbH, Inffeldgasse 13, 8010 Graz, Austria

²Novartis Pharma AG, Novartis Campus, 4056 Basel, Switzerland

³Hosokawa Micron B.V., Gildenstraat 26, 7005 BL Doetinchem, Netherlands

⁴Graz University of Technology, Institute for Process and Particle Engineering, Inffeldgasse 13, 8010 Graz, Austria

In recent years, a lot of effort has been invested by the pharmaceutical industry to move away from batch processing to more agile and flexible continuous manufacturing processes. Going continuous has been discussed and described intensively by academia, industry and regulators, as cost-efficient manufacturing methods and easy up-scaling is strongly demanded. An entire continuous manufacturing plant includes several process steps from API production to the final oral dosage form such as synthesis, crystallization, washing, filtration, drying, milling, blending, granulation and tableting/capsule filling.

After API synthesis the input material for solid dosage form production can be prepared by crystallization through different methods like cooling, evaporation or sublimation. The produced suspension is usually a mixture of several liquids and solids, including the crystallized API. Before drying of the suspension mixture, various washing and filtration steps are involved to purify the drug product. The amount of impurities has to be decreased below a certain threshold to ensure patient safety and drug efficacy. Furthermore, tailored particle properties such as particle size distribution must not be influenced by washing to ensure consistent product quality and process ability within downstream process steps.

A typical washing and filtration process is arranged in cascades to guarantee a highly uniform and pure crystalline material. Therefore, anti-solvent is added in a precisely defined mixing ratio to the mother liquor. An optimal process design is necessary to decrease the number of multiple washing/filtration steps to a minimum to avoid changes of the solid product by mechanical stresses. In addition, considering environmental aspects, energy consumption and production of hazardous waste can be diminished as well.

In this work a newly developed, continuous solvent exchange washing process was established suitable for low throughputs in the range of 2-12 l/h. A robust process design can be shown by means of model substances with a particle size below 100 µm. Variations in the composition of the mother liquid suspension and the washing medium revealed the influence of the solvent exchange washing process on the product particle size distribution. Within the given design space, suitable configurations were achieved for consistent product quality. In the specific case, changes of the particle size distribution were diminished below 15%.