Investigating the Implications of Coexistent Halogen and Hydrogen Bonds on the Physical Stability of Amorphous Solid Dispersions Using Time–Temperature-Transformation Diagrams

Solution nuclear magnetic resonance spectroscopy was used to characterize the interaction landscape between polyvinylpyrrolidone vinyl acetate copolymer (PVPVA) and each of the structurally analogous drug molecules bromopropamide, chlorpropamide, and tolbutamide. Upon the addition of bromopropamide to PVPVA, strong downfield shifts for the hydrogen-bond donors and the carbon adjacent to the bromine confirmed strong, adhesive, coexistent hydrogen (H–) and halogen (X–) bonding interactions. Comparison of H-bonding strength with PVPVA for chlorpropamide and tolbutamide revealed that they were similar; however, the interaction landscape was stronger for chlorpropamide-PVPVA, owing to the formation of additional coexistent X-bonds. Recrystallization onset times (t_crys) were identified using simultaneous X-ray diffraction–differential scanning calorimetry (XRD-DSC) at seven isothermal conditions, and the phase boundaries were built using increasing PVPVA concentrations. The implications of the different interaction landscapes were evaluated with respect to the physical stability of drug-polymer systems using time–temperature-transformation (TTT) diagrams. Across all compositions, bromopropamide had the highest t_crys, followed by chlorpropamide and tolbutamide at lower isothermal temperatures. Conditions at and above the “nose” temperature led to a trend-reversal, resulting in bromopropamide having the lowest t_crys. Identification of the polymorph that grew from the melt using simultaneous XRD-DSC revealed that the unit cells for all analogues were isostructural; bromopropamide had the highest thermal properties, and consequently the highest crystallization tendency.

The physical stability of drug-polymer systems was related to their respective interaction landscapes, and evaluated using time–temperature-transformation (TTT) diagrams.