INCREASED METASTABLE SOLUBILITY OF MILLED GRISEOFULVIN, DEPENDING ON THE FORMATION OF A DISORDERED SURFACE-STRUCTURE

The effect of mechanical processing on the solubility of griseofulvin was studied. Milling of griseofulvin produced an increased metastable solubility. The milling operation did not change the material's bulk thermal properties identifiable by DSC, nor did it alter the surface area or the individual primary particle size, to fully explain the apparent increase in solubility. However, the thermodynamic evaluation of milled griseofulvin showed an increase in free energy and a reduction in the heat of solution. This suggests that the increase in solubility was due to disordering of the solid structure, estimated to be about 5.8% w/w of the total mass and limited only to an external assumed surface layer 40-50 nm in thickness. The initial solubility levels obtained were found to be directly related to the solid solute particle surface structure. The slow decrease from the initially high metastable solubility level to the stable, low equilibrium solubility seemed to be controlled by a surface reaction mechanism, probably a solid-state rearrangement process and not by a solute molecular diffusion in the bulk solution.