Factors influencing the release of poorly water-soluble drugs from solid-dispersion granules during storage

Date of Completion

January 2002


Health Sciences, Pharmacy




There is renewed interest in using solid dispersions to enhance the dissolution rate of poorly water-soluble drugs. However, difficulties in processing and poor physical stability are two key limitations to their widespread commercialization. In this work, a combination of solid dispersion and surface adsorption techniques was explored to overcome these limitations. Ternary solid-dispersion granules incorporating a drug, dispersion carrier, and surface adsorbent were prepared using hot-melt granulation. Gelucire 50/13 and polyethylene glycol (PEG) 8000 were evaluated as low melting point solid dispersion carriers. Neusilin US2 (magnesium aluminosilicate as a spray-dried amorphous powder with high specific surface area, excellent flow, and good compressibility) was used as the surface adsorbent. Processing of these dispersion granules into tablets proved to be quite practical. ^ Other than the dissolution enhancement of poorly water-soluble drug, BAY 12-9566, on formation of dispersion granules, drug dissolution was further enhanced upon storage at 40°C/75% RH. ^ To investigate the generalizability of this phenomenon, a series of proton-donating drugs, including drugs with carboxylic acid moieties (BAY 12-9566, naproxen, ketoprofen, and indomethacin), amide moieties (phenacetin), hydroxyl moieties (testosterone), and a non proton-donating drug (progesterone) were studied. Two competing mechanisms underlie the complex changes observed in drug dissolution upon storage of solid dispersion granules. Conversion of the crystalline drug to the amorphous Neusilin-bound state appeared to increase dissolution, whereas, Ostwald ripening can be used to explain the decrease in drug dissolution upon storage. ^ Drug solubility in Gelucire was a crucial factor in determining the predominant mechanism by governing the flux towards the surface of Neusilin. Thus it appeared that Neusilin was the critical component with Gelucire simply acting as a medium for drug mobility. The feasibility of using a ball mill to facilitate the interaction between Neusilin and drugs was, therefore, investigated. It was possible to convert the drugs to their amorphous states, which showed good physical stability on storage. The water of adsorption mediates the interaction between the drugs and Neusilin. The present study demonstrates two methods and corresponding mechanisms for stabilization against reversion to crystalline state. ^