Development of continuous spatially distributed diafiltration unit operations

Abstract

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 (CSDD) operation is developed herein that aims to conduct continuous single stage diafiltration in a manner that would yield equivalent or better purification efficiency than both batch and incumbent single stage continuous diafiltration configurations. To achieve this goal, a diafiltration solvent is introduced spatially across the membrane unit in a highly uniform manner, with the flow guided by a range of 3D-printed static mixers, developed by CFD informed design, to increase localized mixing of retentate and diavolume flows or displacement effects within the membrane channel. Static mixers were 3D-printed using titanium and polyether ether ketone (PEEK) providing high pressure and chemical compatibility, suited for intensive continuous processes. Ibuprofen was selected as a model active pharmaceutical ingredient (API) with methanol and ethanol used in model impurity removal and solvent swap scenarios with an organic solvent nanofiltration membrane used to selectively retain ibuprofen. Significant improvements in solvent consumption and yield were realized with both CSDD based purification and solvent exchange operations compared to batch diafiltration. As such, CSDD 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 small scale automated flow-based experimentation.