Molecular structure of ketoprofen-polyvinylpyrrolidone solid dispersions prepared by different amorphization methods†

Amorphous solid dispersions (ASDs) are a widely studied formulation approach for improving the bioavailability of poorly water-soluble pharmaceuticals. Yet, a complete understanding remains lacking for how specific processing methods may influence ASDs’ molecular structure. We prepare ketoprofen/polyvinylpyrrolidone (KTP/PVP) ASDs, ranging from 0–75 wt% KTP, using five different amorphization techniques: melt quenching, rotary evaporation with vacuum drying, spray drying, and acoustic levitation with either a premixed solution or in situ mixing of separate co-sprayed solutions. The co-spray levitation approach enables on-demand compositional changes in a containerless processing environment, while requiring minimal pharmaceutical material (∼1 mg). The structure of all ASDs are then compared using high-energy X-ray total scattering. X-ray pair distribution functions are similar for most ASDs of a given composition (R_x = 0.4–2.5%), which is consistent with them having similar intramolecular structure. More notably, differences in the X-ray structure factors for the various amorphization routes indicate differing extents of molecular mixing, a direct indication of their relative stability against crystallization. Melt quenching, spray drying, and levitation of premixed solutions exhibit some degree of molecular mixing, while the co-sprayed levitation samples have molecular arrangements like those of KTP/PVP physical mixtures. These findings illustrate how X-ray total scattering can be used to benchmark amorphous forms prepared by different techniques.