Development of Continuous Spherical Crystallization to Prepare Fenofibrate Agglomerates with Impurity Complexation Using Mixed-Suspension, Mixed-Product Removal Crystallizer

Agglomeration during crystallization, such as spherical crystallization, has the potential to integrate pharmaceutical downstream processes after compound synthesis. This process incorporates granulation and agglomeration during the crystallization process and to date has been performed in batch reactors. However, because it involves certain complicated phenomena, the batch process is difficult to scale up for commercial production. We demonstrate the feasibility of a continuous process of crystallization with agglomeration based on the spherical crystallization of fenofibrate (FF) as a model active pharmaceutical ingredient (API) by using a mixed-suspension, mixed-product removal (MSMPR) crystallizer. The characteristics of FF granules produced by the emulsion solvent diffusion method with MSMPR were compared with the characteristics of batch-prepared FF granules. The particle-size distribution of the FF agglomerates prepared by MSMPR crystallizer was not significantly different from that prepared by the equivalent batch-wise crystallizer. The effects of the operating parameters in MSMPR were examined based on the crystal properties of FF granules produced via continuous spherical crystallization. Conversely, pharmaceutical crystallization mainly is purification to generate pure solid APIs. However, impurity separation in spherical crystallization has not been demonstrated. Impurity inclusion in the crystal lattice is difficult to avoid, especially when the impurity and targeted API molecule structures are similar. Thus, we established effective purification during continuous spherical crystallization using a complexing agent (1,3-di-o-tolylguanidine, DOTG) with a representative impurity (fenofibric acid, FFA) to prevent impurity incorporation into the crystal lattice. Purification improvement using the FFA/DOTG complex was substantiated via continuous spherical crystallization with MSMPR.