Implications of Coexistent Halogen and Hydrogen Bonds in Amorphous Solid Dispersions on Drug Solubility, Miscibility, and Mobility

Specific noncovalent drug-polymer interactions were analytically identified using Raman and Fourier transform infrared spectroscopy for amorphous solid dispersions (ASD) formed between either chlorpropamide or tolbutamide and polyvinylpyrrolidone vinyl acetate random copolymer (PVPVA). Spectral changes in the C-Cl stretching vibrations due to changes in the electronic environment of the Cl atom confirmed halogen bond formation in chlorpropamide-PVPVA ASDs, the extent of which was established to be inversely related to the concentration of the drug using 2D correlation spectroscopy analysis. Hydrogen bonding between the secondary amide of each drug and the pyrrolidone carbonyl of the copolymer was also confirmed in all dispersions. Implications of coexistent interactions were investigated for drug-polymer solubility, mixing free energy, and molecular mobility relative to tolbutamide, which only formed hydrogen bonds with PVPVA. Chlorpropamide had a higher solubility, a larger negative mixing free energy, and lower mobility in PVPVA relative to tolbutamide. These thermodynamic and kinetic differences demonstrate the significance of halogen bond formation even when hydrogen bonding is present.