In Situ Monitoring of the Solvent-Mediated Transformation of Cefadroxil DMF Solvate into Monohydrate

In situ monitoring phase transformation process is of great importance to control the quality of crystalline products. In this paper, the transformation of N,N-dimethylformamide (DMF) solvate into monohydrate of cefadroxil was studied in DMF-water mixtures. The solvates were characterized by several offline methods such as Powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and scanning electron microscope (SEM). Thermodynamic stability of DMF solvate and monohydrate of cefadroxil in DMF-water mixtures were investigated to analyze the relationship between solubility ratio and transformation kinetics at different temperatures, water content and stirring speeds. Results indicate that solubility ratio increases with temperature and water content, which leads to less transformation time. Transformation rate is governed by the growth of cefadroxil monohydrate and process parameters must be controlled based on in situ techniques to prepare high quality products. According to process analysis results by SEM, the mechanism of transformation was interpreted as the surface nucleation of monohydrate.