Spatial-thermodynamic understanding of stabilization mechanism using computational approaches and molecular-level elucidation of the mechanism of crystal transformation in polymorphic irbesartan nanosuspensions

Irbesartan polymorphisms possess low solubility properties, nanosuspensions represent a method for improving the dissolution. Stabilizers are significant constituents of nanosuspensions. Herein we presented computational research on screening stabilizers and exploring stabilization mechanisms. The crystal transformation mechanism was also investigated. Soluplus-P407 and TPGS-HPMCE5 were screened by spatial conformation and thermodynamic energy analyses. The prepared nanosuspensions improved the dissolution properties of bulk drugs at pH 1.2, 4.5, 6.8. The nanosuspensions stabilization mechanism was analyzed by Molecular docking, Molecular dynamics simulations, Fourier transform infrared spectroscopy and Raman spectroscopy. It might be relate to the decreased enthalpy and Gibbs free energy which were determined by the synergy of external and internal energy factors. The X-ray powder diffraction, differential scanning calorimetry, scanning electron microscopy and transmission electron microscopy showed the crystal structures. The irbesartan B form was transformed in a Soluplus-P407-B/TPGS-HPMCE5-B physical mixture, but not in an SDS (-OH free)-B physical mixture. The intraproton transfer induced by -OH on the stabilizer might be the transformation mechanism.