ANDREA ADAMO, TREVOR MURRAY
Zaiput Flow Technologies, LLC, Waltham, United States

Abstract

Liquid-liquid Extraction (LLE) is an often overlooked process step that can lead to different bottlenecks during scale up and production of a wide range of pharmaceuticals, fine chemicals and specialty chemicals in both batch and flow. Often, this slow process requires waiting for a biphasic system to gravity separate out, a method that can take hours to days to accomplish. Furthermore, this settling is often carried out in the same reactor in which the product is made. As a result, valuable reactor space is left unused during a reaction just to accommodate, later on, the extraction solvent. This results in a substantial reduction of plant’s productivity.

Through the use of technology, these hurdles (reduced reactor productivity, slow settling) can be overcome by taking the extraction out of the reactor and into a flow through extraction unit. By combining in-line mass transfer with continuous membrane separation, extractions can now be carried out in significantly less time, while doubling the capacity of the reactor. Here we discuss how this “hybrid” batch/continuous processing can be used to leverage existing batch assets and facilitate the transition to fully continuous processing.

Liquid-liquid extraction (LLE) is the most common post reactive workup step in pharmaceutical production and an equally important step in many other industries, yet it is often overlooked by process development teams rushing to get a process to market. Most often LLE is carried out in the batch reactor after a reaction has taken place. Typically, a first mixing step needed to reach equilibrium between the phases, is followed by a phase separation driven by gravity. The process mimics what done in the lab with shaker flasks or separatory funnel.

While this methodology of batch-based liquid-liquid extraction has been used for a century or so, it is very much open to improvements as the settling process may take hours to days to complete depending on the complexity of the solution. Other challenges typically arise including rag layers and dark/dark phases, which make finding the liquid-liquid interface difficult and lead to product losses. An important, often overlooked issue that arises in batch-based extraction is the wasting of valuable asset: the reactor itself. These reactors are often used at half capacity so that the wash or extraction following the re ...