Achieving New Scales: The First Successful Pilot Plant Spherical Crystallization

Spherical crystallization is a widely used technique for the preparation of spherically shaped agglomerates of crystalline material, which results in free-flowing powders with improved micromeritic properties. In this study, we applied this technique to the reactive crystallization of 3-iodo-7-methyl-1H-indazole, a critical early intermediate for one of our Active Pharmaceutical Ingredients at Boehringer Ingelheim. We utilized a traditional spherical agglomeration approach to identify a bridging liquid that could be easily implemented into the current crystallization process. Our experiments showed that the amount and rate of antisolvent addition were important for the crystallization; however, the stir rate and the amount of bridging liquid were the most critical factors. We successfully scaled up this process to a 300 L pilot plant reactor, keeping a constant power per unit mass during scale-up. The results showed that the spherical crystallizations for both 300 L batches were highly successful with almost identical particle sizes.