Synergistic Regulation of Water Activity on the Polymorphs and Crystal Morphology of Ampicillin Sodium

In this work, the synergistic mechanism by which water activity regulates the polymorphic transformation and crystal habit of ampicillin sodium crystals was elucidated, and the crystal structure of form D was determined. Water activity was calculated based on the NRTL equation to determine the critical range for polymorphic transformation. Online Raman spectroscopy, PXRD, FTIR, molecular dynamics simulation, and other techniques were used in combination to reveal the effects of solvent composition, solid content, and temperature on the polymorphic transformation process and crystal habit. It was found that anhydrous form B with aggregated morphology is formed at low water activity, while the crystals transform into form D at high water activity, exhibiting improved dispersibility and a large, flake-like morphology. Increasing water activity could enhance solvent adsorption on various crystal faces, weaken intermolecular aggregation of the solute, and then result in crystals with improved dispersibility and flake-like morphology. By regulating the interactions between solvent molecules and crystal faces, water activity achieves the coordinated transformation of ampicillin sodium polymorphism and crystal habit, providing a reliable theoretical basis for the optimization of crystal forms and morphologies of β-lactam antibiotics.