(58d) Development of a Novel Continuous Spatially Distributed Diafiltration Unit Operation

Flow chemical and continuous processes have seen significant uptake in R&D and small intensified manufacturing for complex chemical and pharmaceutical products. However, continuous work-up and purification operations for continuous manufacturing requires further development to approach the significant level of purification and stream adjustment in multistep routes that batch synthesis traditionally offers in the production of these classes of chemical products.

The objective of this study is to develop an operation that can conduct separations based on diafiltration using semipermeable nanofiltration or ultrafiltration membranes in a fully continuous manner in a single stage configuration. To this end a Continuous Spatially Distributed Diafiltration (CS2D) operation was developed, to conduct straight through diafiltration in a manner that would yield equivalent or better purification efficiency, yield and productivity to batch diafiltration. To achieve this goal diafiltration solvent is introduced spatially in a highly uniform manner with the flow guided by a range of 3D-printed mixers designed using CFD informed design to increase localized mixing of retentate and diavolumes flows or displacement effects within the channel. Static mixers were 3D-printed using titanium and polyether ether ketone (PEEK) providing high pressure and chemical compatibility (Figure 1), suitable for many flow chemical separations.

Figure 1: (a) mixer filled membrane flatform (1-bottom plate; 2- middle plate to hold membrane with double O-ring; 3-mixer; 4-top plate) and (b) selection of printed mixers

Ibuprofen was selected as a model active pharmaceutical ingredient (API) with methanol acting as a solvent and ethanol used as a model impurity where an organic solvent nanofiltration membrane was used to selectively retain ibuprofen. Experiments were processed at a 55 bar transmembrane pressure at which 87% and 15% rejection coefficients of ibuprofen and ethanol were determined respectively, in screening experiments. Using 4 diavolumes in constant volume diafiltration in batch and CS2D runs, purities of 55% and 76% were obtained at equivalent yields of approximately 61% for the Batch and CS2D separation respectively. Demonstrating that continuous spatially distributed diafiltration (CS2D) can match or exceed results conducted in equivalent batch configurations. As such CS2D may present an attractive intermediate purification and solvent swap operation for telescoped flow chemical and continuous processing applications, in addition to a highly compatible platform for use in automated flow-based experimentation.

Acknowledgements

This publication is supported SSPC, the Science Foundation Ireland Research Centre for Pharmaceuticals (12/RC/2275_P2) and I-form the Science Foundation Ireland Centre For Advanced manufacturing (16/RC/3872) and TIDA, SFI/EI Technology Innovation Development award (16/TIDA/4003) co-funded under the European Regional Development Fund.