(322b) Continuous Centrifugal Extraction for Intermediate Recovery from a Biocatalysis Reaction

Continuous processing, or flow chemistry, has started to transform the way pharmaceuticals are made over the past decade. The flexibility, reduced footprint, enhanced control strategies, and process intensification capabilities offered by continuous unit operations are a convincing case for transitioning certain processes from batch to flow. Everything from reactions, liquid-liquid extraction (LLE), purification, crystallization, and tableting processes are being developed in flow with the goal of achieving new chemistries not possible in batch as well as increasing economic savings and safety. Pfizer is working to develop continuous processes through a concerted effort at all levels across our organization, from R&D through full-scale commercial production.

Recent work that utilized continuous LLE coupled with phase separation enabled via centrifugal extraction will be presented. Performing reactions in flow is not sufficient if the subsequent work-up steps are done in batch. This is particularly true for gravity separation when phases can take days or weeks to separate, or when stable emulsions can form a thick rag layer at the liquid-liquid interface. This work will describe the use of a lab-scale centrifugal extractor to separate a post-enzymatic reaction mixture consisting of 2.5 wt% enzyme/protein, water, MTBE, and reaction intermediate.

This process was chosen since this reaction mixture was prone to forming emulsions and took several days to separate via gravity separation. The batch process also involved several protein pre-treatment steps, including low pH denaturation, addition of celite or carbon filter aid, and coarse filtration, before performing the extraction and separation at an elevated pH. The intermediate was sensitive to both low and high pH conditions, which could only be mitigated via sequestering the intermediate into the organic phase, preferably without significant agitation.

Three processing routes were trialed, two which eliminated one or more pre-treatment steps and one which maintained the same pre-treatment as the batch route. Successful extraction and phase separation was demonstrated for all three routes, including the most challenging route which included no pre-treatment. The results for the most successful route were scaled up from our lab unit, which had a 2.2 mL bowl volume (up to 33.3 mL/min throughput), to a larger pilot plant sized unit with a bowl volume of 80 mL (up to 1000 mL/min throughput). A discussion on the scale-up parameters and throughput capabilities of this technology will also be discussed.