Clarification of the Dissolution Mechanism of an Indomethacin/Saccharin/Polyvinylpyrrolidone Ternary Solid Dispersion by NMR Spectroscopy

Abstract

Here, an indomethacin (IMC)/saccharin (SAC)/polyvinylpyrrolidone (PVP) ternary solid dispersion (SD) prepared by spray-drying was characterized to clarify its dissolution mechanism. Solid-state NMR spectroscopy revealed that IMC and SAC in the ternary SD interacted via hydrogen bonding in a similar manner as that in the IMC/SAC co-crystal. Initial IMC dissolution from the ternary SD was slower than that from the binary SD, although IMC supersaturation was maintained for a relatively longer time in the ternary SD. Solid- and solution-state NMR measurements for dispersed particles in the dissolution test revealed that the particle for IMC/PVP binary SD was composed of amorphous IMC dispersed in PVP matrix and α-form IMC. In contrast, the particles for the ternary SPD was composed of amorphous IMC dispersed in PVP matrix and IMC/SAC co-crystals. Scanning electron microscopy indicated that in the binary SD, amorphous IMC microfiber-gel was generated on the surface of particles after the dissolution test, preventing amorphous IMC from contacting with water. In contrast, in the ternary SD, IMC/SAC co-crystals were generated on the surface of particles, and intermediate spaces were formed on the surface, which allowed water intrusion into the particles and continuous dissolution of IMC.

Keywords: Cocrystal; Dissolution; Nuclear magnetic resonance spectroscopy; Scanning electron microscopy; Solid dispersion; Solid-state NMR spectroscopy; Supersaturation.