Recently, development and elaboration of the unit operations necessary to implement continuous manufacturing of APIs and Drug Products have been being widely practiced successfully. However, fouling and clogging of lines in both continuous crystallization and flow chemistry still present a challenge in designing continuous processes. These persistent challenges are significant in handling slurries, traditional powder operations, and solid processing.
This work presents a novel unit operation designed to eliminate the need for slurry handling in the API manufacturing by utilization of a dynamic (falling) film based solution layer crystallization technique. Crystallization on an immobilized layer allows purification, solvent swapping and concentration of intermediate and final API streams to be conducted without the need for isolation or conveying of slurry or powder. In addition, in coupled with a powder free formulation operation this operation could facilitate the elimination of solids handling in drug manufacturing process altogether.
The results for different APIs and crystallization systems prove the performance of the technique for different process parameters, with high yield and level of purification, at high throughput and short processing (residence) time. In addition to the experimental results, a mathematical modeling study demonstrates the performance of the technique for different process parameters (temperature, flow-rate, supersaturation, growth-rate, and distribution coefficient) and the flexibility of the techniques for various process combinations, such as parallel, series, and scaled up/down.