Continuous Hydrolysis and Liquid–Liquid Phase Separation of an Active Pharmaceutical Ingredient Intermediate Using a Miniscale Hydrophobic Membrane Separator

Abstract

Continuous hydrolysis of an active pharmaceutical ingredient intermediate, and subsequent liquid−liquid (L-L) separation of the resulting organic and aqueous phases, have been achieved using a simple PTFE tube reactor connected to a miniscale hydrophobic membrane separator. An alkoxide product, obtained in continuous mode by a Grignard reaction in THF, reacted with acidic water to produce partially miscible organic and aqueous phases containing Mg salts. Despite the partial THF− water miscibility, the two phases could be separated at total flow rates up to 40 mL/min at different flow ratios, using a PTFE membrane with 28 cm 2 of active area. A less challenging separation of water and toluene was achieved at total flow rates as high as 80 mL/min, with potential to achieve even higher flow rates. The operability and flexibility of the membrane separator and a plate coalescer were compared experimentally as well as from a physical viewpoint. Surface tension-driven L-L separation was analyzed in general terms, critically evaluating different designs. It was shown that microporous membrane L-L separation can offer very large operating windows compared to other separation devices thanks to a high capillary pressure (Laplace pressure) combined with a large number of pores per unit area offering low pressure drop. The separation device can easily be operated by means of a back-pressure regulator ensuring flow-independent separation efficiency. Simple monitoring and control strategies as well as scaling-up/out approaches are proposed, concluding that membrane-based L-L separation may become a standard unit operation for continuous pharmaceutical manufacturing.

The route from problem to solution in multistep continuous flow synthesis of pharmaceutical compounds

“…15), when the product remains in the mother liquor, while the solid impurities are retained on the filter material (and then discarded by an appropriate mechanism). 27 There are several examples of extraction methods using liquidliquid phase separation 96,97 to eliminate the excess of the reagents, 21,65 co-products, 65 traces of solvents 39,80 or cosolvents, 29 which have been used in a previous step. Complete removal of water may require a column filled with solid MgSO 4 desiccant after the phase separation, as exemplified in the flow preparation of Milnacipran analogs.…”

A Microfluidic Toolbox for the Development of In-Situ Product Removal Strategies in Biocatalysis

“…Focusing on liquid-liquid separations, a very rapid, simple, and robust method could be developed for separating two immiscible liquids. CerveraPadrell and coworkers [82] performed successful separation of toluene and water by applying a suitable PTFE membrane at microscale. Li and coworkers [83] designed a more sophisticated setup that continuously recycled homogeneous palladium catalyst by applying liquid-liquid phase separation and permeable membranes.…”

Continuous‐Flow Multistep Synthesis of Cinnarizine, Cyclizine, and a Buclizine Derivative from Bulk Alcohols

“…[34,35] To see the potential in the application of continuous chloride synthesis, we connected the product stream of theb enzyl chloride forming reactiont oasecond reactor in which another nucleophilic substitution would take place.T he connectionr elied on continuous inline liquid-liquid separation, which occurred in aT eflon-membrane-based separator.Similarseparators have been used previously in multistep continuous syntheses. [36][37][38] The designa nd operation of this separator is described in the Supporting Information. For ac omplete separation, the correct pressure differences hould be appliedo vert he membrane to allow permeate to pass through the membrane without causing ab reakthrough of the retained phase,o ra lternatively, without carrying the permeate within the retentate.…”