Experimental Investigation Of An Integrated Crystallization And Wet-Milling System With Temperature Cycling To Control The Size And Aspect Ratio Of Needle-Shaped Pharmaceutical Crystals

Control of crystal size distribution (CSD) and shape is critical in the pharmaceutical industries for meeting tight critical quality attribute (CQA) requirements in the manufacturing of active pharmaceutical ingredients (APIs). In general, to increase the efficiency of downstream operations such as filtration and drying, and increase the flowability and manufacturability of powders, large crystals with a low aspect ratio (AR) are preferred. Large AR, needle-shaped crystals are very common in the pharmaceutical industries; consequently, to achieve desired manufacturability performance, a careful design of the crystallization processes is required. In this work, the systematic design of a crystallization process for an API (compound A) from Takeda Pharmaceuticals International Co. is demonstrated. The challenges related to the crystallization of compound A include that the process is nucleation dominated by slow growth rates, which necessitates intermittent internal fines removal via temperature cycling. Moreover, compound A tends to form high AR crystals, which can cause manufacturability problems. The aim of the crystallization design is to produce low AR (<3) and sufficiently large crystals with narrow distributions. Two methods were applied to reach these goals: (1) application of immersion milling to further control the shape and size of crystals and (2) application of temperature cycles to internally remove the fines. It is also demonstrated that these approaches can be implemented in an unseeded crystallization without compromising the product quality.