(126e) Scale-up of a Continuous Extraction Process for an Equilibrium-Limited Reaction

Scale-Up
of a Continuous Extraction Process for an Equilibrium-Limited Reaction

Eric
G. Moschetta^*,1, Michael T. Tudesco¹, and Eric A. Voight²

¹AbbVie, Inc.
Process R&D, 1401 Sheridan Road North Chicago, IL 60064

²Discovery
Chemistry and Technology, AbbVie, Inc., 1 North Waukegan Road, North Chicago,
Illinois 60064

^*corresponding
author: eric.moschetta@abbvie.com

            Continuous
processing is an emerging paradigm the pharmaceutical industry because of the
potential improvements in cycle time and the final quality and yield of the
desired product. Flow chemistry is perhaps the most popular method for
implementing continuous processing the pharmaceutical industry to date, but
impacts in continuous separation and isolation of API have enormous potential
to offer improvements in process efficiency. One especially fruitful area of
continuous processing is liquid-liquid extraction. In the pharmaceutical
industry, liquid-liquid extraction is executed batch-wise on the manufacturing
scale, almost exclusively. The execution of multiple batch extractions on the
manufacturing scale is often inefficient, expensive, and labor-intensive.
Developing and implementing continuous liquid-liquid extraction processes
represents significant reductions in processing time and solvent use.
Additionally, continuous extraction offers flexibility in terms of the choice
of contacting device and can be fit to the needs of the process in question,
whether the separation involves handling emulsions, separating liquids of similar
densities, etc. Therefore, it is critical to identify opportunities to develop
and implement continuous liquid-liquid extractions for improving processing
efficiency from the laboratory scale all the way to manufacturing.

            We
present the design and implementation of a fit-for-purpose continuous
liquid-liquid extraction for the scale-up of an equilibrium-limited reaction.
This fit-for-purpose approach is easily adaptable to a number of equilibrium
reactions, can be customized to fit the needs of the process, and requires
simple laboratory glassware and equipment to implement. We show how the process
parameters were varied to reduce the overall amount of extraction solvent
needed to drive the reaction to completion. Our method is ideally suited to
situations where both material and time are limited. We implemented our
continuous extraction for ABBV-168, a 2′-bromouridine for the treatment
of Hepatitis C, and demonstrated scale-up in the laboratory up to 50 g, having
developed the process on the 0.5-5 g scales.

All
authors are employees of AbbVie and may own AbbVie stock. AbbVie sponsored and
funded the study; contributed to the design; participated in the collection,
analysis, and interpretation of data, and in writing, reviewing, and approval
of the final publication.