Prediction of dissolution-absorption relationships from a dissolution/Caco-2 system.

While the analysis of in vitro dissolution-in vivo absorption relationships from oral solid dosage forms provides biopharmaceutical insight and regulatory benefit, no well developed method exists to predict dissolution-absorption relationships a priori to human studies. The objective was to develop an integrated dissolution/Caco-2 system to predict dissolution-absorption relationships, and hence the contributions of dissolution and intestinal permeation to overall drug absorption for fast and slow formulations of piroxicam, metoprolol, and ranitidine. Dissolution studies were conducted on fast and slow dissolving immediate-release formulations of piroxicam, metoprolol tartrate, and ranitidine HCl. Dissolution samples were treated with concentrated buffers to render them suitable (i.e., isotonic and neutral pH) for Caco-2 monolayer permeation studies. The dissolution/Caco-2 system yielded a predicted dissolution-absorption relationship for each formulation which matched the observed relationship from clinical studies. The dissolution/Caco-2 system's prediction of dissolution or permeation rate-limited absorption also agreed with the clinical results. For example, the dissolution/Caco-2 system successfully predicted the slow piroxicam formulation to be dissolution rate-limited, and the fast piroxicam formulation to be permeation rate-limited. Moreover, the system predicted this change from dissolution rate-limited absorption for slow piroxicam to permeation rate-limited absorption for fast piroxicam, in spite of piroxicam's high permeability and low solubility. The dissolution/Caco-2 system may prove to be a valuable tool in formulation development. Broader evaluation of such a system is warranted.