Thermal melt synthesis and structural reorganization of co-amorphous lidocaine–indomethacin studied by near infrared and terahertz spectroscopy

Abstract

This study reports a novel process analytical methodology for monitoring thermal co-amorphization of lidocaine (LID) and indomethacin (IMC) by combining in situ near infrared (NIR) spectroscopy, terahertz (THz) spectroscopy, and chemometric analysis. The novelty of this work lies in the real-time, in situ monitoring of molecular-level structural reorganization during thermal co-amorphization, enabling identification of transient intermediate states that have not been previously reported. Unlike conventional approaches that characterize co-amorphous systems only at fixed end-point states, we continuously monitored molecular-level structural reorganization during heating from 30°C to 80°C in real time, enabling identification of transient intermediate states and phase separation behavior. The co-amorphous LID–IMC materials were synthesized by thermal melt synthesis at 80°C, as indicated by broad powder X-ray diffraction patterns. In situ NIR spectral measurements during heating were analyzed using machine learning techniques, revealing that the mixture underwent separation into two distinct components with generation of intermediate states during co-amorphous formation. FTIR spectroscopy indicated the dissociation of indomethacin dimers and their subsequent binding with lidocaine. Terahertz spectroscopy revealed temperature-dependent structural reorganization, with distinct vibrational modes observed at cryogenic and room temperatures, including a thermally stable mode at 4.90 THz. This combined NIR–THz approach suggests a novel quality control methodology for co-amorphization processes in pharmaceutical applications, offering real-time, non-contact monitoring of structural transformations during production cycles.