Continuous Preparation of APIs in a Tubular Crystallizer

The particle size and the particle size distribution (PSD) of active pharmaceutical ingredients are of crucial interest because the bioavailability is strongly affected by size effects. Furthermore, crystal shape, size, and the crystal size distribution (CSD) have great impact on the properties of powders and bulk solids including flow, packing, mixing, and segregation properties. Crystallization is a way to manipulate the particle size and the PSD. Currently, most crystallization processes of active pharmaceutical ingredients (APIs) are carried out batch wise, which can lead to non-uniform product quality. Therefore, the pharmaceutical industry is currently attempting a transition towards continuous manufacturing in several areas, driven by the “PAT” and the “Critical-path” initiatives of the FDA (Federal Drug Administration). We present a continuously operated tubular crystallizer system, which allows the crystallization of pharmaceutical substances under controlled conditions. Moreover, the crystals in the tubular crystallizer experience less mechanical stress than they would be exposed to in a stirred tank. This ultimately minimizes friction effects and reduces fines production. Thus, a narrow CSD can be achieved. As a model system we have chosen the crystallization of acetylsalicylic acid (ASA) in ethanol. In the figure (a) seeds and (b) product crystals are shown.