Cefixime

In the present study, a novel FTIR-based strategy was introduced to elucidate the role of thermally driven modulations in the structural sustainability of solid-state cefixime. The manuscript established, a mechanistic link between thermally driven free energy modulations and the sequential solid-state transformations in molecular structure of Cefixime, for the first time. We introduced a novel approach that synergistically combine two-dimensional (2D) -FTIR analysis and FTIR deconvolution strategies to sequentially resolve subtle, molecular-level transformations induced by thermal stress (40-90 °C). The asynchronous 2D-COS spectrum identified a critical cross peak at ∼1049-1770 cm^-1, indicated lactonization of the hydrolyzed β-lactam ring as a secondary degradation pathway. The deconvolution and kinetic results revealed that degradation followed a distinct sequence initiated by the cleavage of the carboxymethoxyimino side chain (lowest activation energy, E_a = 34.53 kJ/mol), followed by rupture of the β-lactam ring (E_a = 40.59-57.06 kJ/mol), collapse of the zwitterionic structure (E_a = 65.92 kJ/mol), and finally decarboxylation of the dihydrothiazine ring core (E_a = 79.30 kJ/mol). Spectral deconvolution further validated these steps, highlighting key vulnerabilities in the molecular structure. The molecular structural insights derived from the FTIR strategies were further validated with conclusive evidence from ¹H NMR studies. The integration of FTIR spectroscopy with activation energy calculations provided a quantitative energy landscape of degradation, demonstrating that early side-chain destabilization, which lowered the energy barrier for subsequent core degradation. The degradation of cefixime molecule was a cascade process, where the destabilization of the most labile group (the side chain) lowered the energy barrier for the degradation of the next most unstable group (the β-lactam ring) and followed an order of decarboxylation of the dihydrothiazine ring (least unstable) > collapse of the zwitterionic structure ≫ rupture of the β-Lactam ring > cleavage of carboxymethoxyimino side chain (most unstable). The work, described in the manuscript, established FTIR as a powerful and gold standard for the hierarchical energy landscape of solid-state API degradation and providing a mechanistic blueprint for the rational design of stable cephalosporin formulations.