Effect of drug–polymer interactions on the aqueous solubility of milled solid dispersions

Abstract

The role of molecular interactions in ball milled solid dispersions in determining the aqueous solubility of the poorly water-soluble drug, griseofulvin (GF) has been examined. Ball milled solid dispersions of GF and hydroxypropylmethylcellulose acetate succinate (HPMCAS) and GF and polyvinylpyrrolidone (PVP) were prepared and characterized by laser diffraction, scanning electron microscopy and X-ray powder diffraction and the aqueous saturation solubility measured and analyzed using one way ANOVA. The results showed that solid dispersions of GF and HPMCAS possessed an aqueous GF saturation solubility of about ten times higher than the GF solubility achieved from PVP-based solid dispersions. Furthermore, although the aqueous solubility of GF did not vary with the milling conditions used to prepare the solid dispersions with PVP, significant changes in solubility were observed upon changing the milling conditions for preparation of the GF/HPMCAS solid dispersions. Surprisingly, the GF/HPMCAS solid dispersion prepared using spray drying exhibited a significantly lower aqueous solubility than those prepared by bead milling despite their smaller particle size and GF being fully in its amorphous form. It is thought that the higher surface energy of the spray-dried solid dispersions negatively affected the aqueous solubility of GF. In conclusion, the results suggest that the molecular interactions occurring between GF and HPMCAS affect the aqueous solubility of GF and that the molecular interactions appear to remain in the liquid state. In contrast no molecular interactions were evident in the GF/PVP solid dispersions.