Application of Process Analytical Technology-Based Feedback Control for the Crystallization of Pharmaceuticals in Porous Media

The purpose of this work is to implement a feedback control approach during the cooling crystallization of paracetamol (PCM) in porous media to increase the amount of PCM in the alginate beads (i.e., drug loading) and minimize the heterogeneous nucleation occurring in the bulk system. Two types of cooling profiles were considered: fast linear and programmed cooling. In addition, the model-free direct nucleation control (DNC) strategy was evaluated and compared to controlled cooling crystallization scenarios. A mean drug loading from 49 to 69% was achieved through the various scenarios. The application of DNC increased or maintained the mean drug loading achieved compared to that of the cooling-only scenarios, while a decrease of about 75% was observed in the batch-to-batch variability. This work demonstrates the benefits of using feedback control approaches to increase drug loading, decrease batch-to-batch variability, and control dissolution behavior of drug-loaded polymer microspheres.