Real-Time Monitoring of Crystallization Processes Using a Novel Compact Composite Sensor Array

Compact composite process analytical technology (PAT) probes have been identified as a priority to alleviate space constraints in milliliter-scale crystallizers to mitigate their impact on hydrodynamics. Real-time monitoring of the liquid and solid phases in crystallization processes is vital to ensure the critical quality attributes of the crystallized material, including consistently obtaining the solid form. In this proof-of-principle study, a compact composite sensor array (CCSA, 380 × 30 mm housing [length × diameter, 7 mm probe head diameter] that combines ultraviolet (UV) and near-infrared (NIR) features at four different wavelengths (280, 340, 600, and 860 nm) as well as temperature measuring capabilities was evaluated. Flufenamic acid (FFA), a polymorphic compound with an enantiotropic relationship between its forms I and III, was used as the model API. The results indicate that the CCSA similarly to an established Raman spectrometer monitors the significant inflection points (timestamps) for three batch cooling crystallization processes: (1) spontaneous nucleation, (2) seeded, and (3) solvent-mediated polymorphic phase transformation (SMPT). Ultimately, the data presented in this study prove that the CCSA might be used as a cost-effective process analyzer to routinely monitor qualitatively crystallization processes while addressing the need for compact PATs suitable for small-scale set-ups.