Monitoring of Paracetamol Solvent-Mediated Phase Transformation in Seeded Batch Crystallization Processes

Abstract

Polymorphism control in crystallization processes is critical for ensuring the final quality of active pharmaceutical ingredients (APIs). In the present research, the solvent-mediated phase transformation (SMPT) of paracetamol, a widely used API, from its metastable form II to the stable form I during seeded batch cooling crystallization in isopropyl alcohol/water solution is investigated. The study explores the utility of offline FT-NIR spectroscopy and an inline PAT Blaze900 probe to detect paracetamol polymorphs and monitor polymorphic changes. Key findings demonstrate that FT-NIR offers a robust offline alternative for polymorphism detection and monitoring. The PAT Blaze900 recordings, in terms of chord length counts and distributions, also provide additional information about form II SMPT and are in accordance with the FT-NIR prediction model output. The SMPT kinetics are influenced by operational parameters such as supersaturation and operational and cooling temperature. Optimization of these parameters enabled better control over the SMPT kinetics, paving the way for efficient stabilization of paracetamol metastable form II to 30 min before complete conversion to the most stable form I.