Investigating the\nImplications of Coexistent Halogen\nand Hydrogen Bonds on the Physical Stability of Amorphous Solid Dispersions\nUsing Time–Temperature-Transformation Diagrams

Solution nuclear magnetic resonance spectroscopy was\nused to characterize\nthe interaction landscape between polyvinylpyrrolidone vinyl acetate\ncopolymer (PVPVA) and each of the structurally analogous drug molecules\nbromopropamide, chlorpropamide, and tolbutamide. Upon the addition\nof bromopropamide to PVPVA, strong downfield shifts for the hydrogen-bond\ndonors and the carbon adjacent to the bromine confirmed strong, adhesive,\ncoexistent hydrogen (H–) and halogen (X–) bonding interactions.\nComparison of H-bonding strength with PVPVA for chlorpropamide and\ntolbutamide revealed that they were similar; however, the interaction\nlandscape was stronger for chlorpropamide-PVPVA, owing to the formation\nof additional coexistent X-bonds. Recrystallization onset times (<i>t</i><sub>crys</sub>) were identified using simultaneous X-ray\ndiffraction–differential scanning calorimetry (XRD-DSC) at\nseven isothermal conditions, and the phase boundaries were built using\nincreasing PVPVA concentrations. The implications of the different\ninteraction landscapes were evaluated with respect to the physical\nstability of drug-polymer systems using time–temperature-transformation\n(TTT) diagrams. Across all compositions, bromopropamide had the highest <i>t</i><sub>crys</sub>, followed by chlorpropamide and tolbutamide\nat lower isothermal temperatures. Conditions at and above the “nose”\ntemperature led to a trend-reversal, resulting in bromopropamide having\nthe lowest <i>t</i><sub>crys</sub>. Identification of the\npolymorph that grew from the melt using simultaneous XRD-DSC revealed\nthat the unit cells for all analogues were isostructural; bromopropamide\nhad the highest thermal properties, and consequently the highest crystallization\ntendency.