The effects of disordered structure on the solubility and dissolution rates of some hydrophilic, sparingly soluble drugs

The effects of experimental design on the apparent solubility of two sparin gly soluble hydrophilic compounds (barium sulphate and calcium carbonate) w ere studied in this paper. The apparent solubility appeared to be primarily dependent on the amount of solute added to the solvent in each experiment, increasing with increased amounts. This effect seems to be due to the exis tence of a peripheral disordered layer. However physico-chemical methods us ed in the present study were not able to unambiguously verify the existence of any disorder in the solid state structure of the drugs. At higher propo rtions of solute to solvent, the solubility reached a plateau corresponding to the solubility of the disordered or amorphous molecular form of the mat erial. Milling the powders caused the plateau to be reached at lower propor tions of solute to solvent, since this further disordered the surface of th e drug particles. It was also found that the apparent solubility of the dru gs tested decreased after storage at high relative humidities. A model for describing the effects of a disordered surface layer of varying thickness a nd continuity on the solubility of a substance is presented. This model may be used as a method for detection of minute amount of disorder, where no o ther technique is capable of detecting the disordered structure. It is sugg ested that recrystallisation of the material occurs via slow solid-state tr ansition at the surface of the drug particle; this would slowly reduce the apparent solubility of the substance at the plateau level to the thermodyna mically stable value. A biphasic dissolution rate profile was obtained. The solubility of the disordered surface of the particles appeared to be the r ate-determining factor during the initial dissolution phase, while the solu bility of the crystalline core was the rate-determining factor during the f inal slower phase. (C) 1999 Elsevier Science B.V. All rights reserved.