(479b) Separation and Purification of Active Pharmaceutical Ingredients via continuous Membrane Filtration

The Food and Drug Administration (FDA) has set strict limits on the purity and composition of pharmaceutical drug formulations to protect consumers. Thus, during the manufacture of active pharmaceutical ingredients (APIs), as-synthesized drugs must be thoroughly separated and purified from the final synthetic mother-liquor for incorporation in a packaged-dose formulation. These purification processes are generally accomplished via a series of iterative batch processing steps including (I) precipitation, (II) filtration, (III) drying, (IV) washing, and (V) redissolving steps. In industry this process is typically relegated to a diverse series of multi-step batch processes involving filter dryers and agitated Nutsche filters which are not amenable to continuous API manufacturing. While recent advances in continuous flow chemistry have enabled the synthesis of APIs in tubular flow reactors, separation and purification steps have lagged in development. State-of-the-art continuous API purification strategies are not truly continuous; they instead utilize a series of semi-batch filter dryer processes in parallel for API purification which are then fed into storage tanks for down-stream processing. These inefficiencies offer ample opportunities for process intensification via truly continuous membrane filtration.

This talk investigates an innovative membrane filtration method of continuously separating and purifying APIs in flow. These feasibility studies will be utilized in a continuous manufacturing system that will enable synthesis and purification of active pharmaceutical ingredients (APIs) from raw materials and provide packaged doses of the finished product. By use of continuous membrane separation, we demonstrate methods of process intensification which reduce the number of filter dryer steps and overall time necessary to achieve pure APIs. Our results highlight size-exclusion membrane studies with a case-study demonstration for the continuous purification of albuterol sulfate, a drug on the FDA shortage list. Additionally, a series of analytical techniques are used to validate product quality; these techniques include high performance liquid chromatography (HPLC), Raman spectroscopy, and UV-Vis spectroscopy. This newly developed separation method will be incorporated into a continuous, end-to-end system and facilitate increased product quality and throughput at reduced costs.