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 t hermal properties identifiable by DSC, nor did it alter the surface ar ea or the individual primary particle size, to fully explain the appar ent increase in solubility. However, the thermodynamic evaluation of m illed griseofulvin showed an increase in free energy and a reduction i n 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 surf ace layer 40-50 nm in thickness. The initial solubility levels obtaine d were found to be directly related to the solid solute particle surfa ce structure. The slow decrease from the initially high metastable sol ubility level to the stable, low equilibrium solubility seemed to be c ontrolled by a surface reaction mechanism, probably a solid-state rear rangement process and not by a solute molecular diffusion in the bulk solution.