Effect of pH on the in vitro dissolution and in vivo absorption of controlled-release theophylline in dogs.

Dogs were used to examine the effect of elevated gastric pH on the absorption of controlled-released theophylline dosage forms with pH-dependent dissolution. In vitro studies showed that a controlled-release theophylline tablet dissolved more rapidly if it was initially exposed to an acidic media. In contrast, a controlled-release theophylline beaded capsule was slightly more rapidly dissolved in the absence of an initial exposure to an acidic media. Gastric pH was increased from 0.5-2.5 to 4.5-7.0 in four dogs by using 150-mg ranitidine HCl tablets, administered every 3 h, to induce an achlorhydric condition. Gastric pH was monitored using a Heidelberg capsule. Ranitidine was shown to have no apparent effect on the absorption or clearance of theophylline administered to the dogs as an oral liquid. The mean area under the concentration-time curve to infinity (AUCinf) for the controlled-release theophylline tablet was 21% greater (p less than 0.05) when administered to the four dogs without ranitidine treatment, compared with that following dosing with ranitidine. In contrast, the controlled-release beaded capsule exhibited a 10% greater AUCinf when ranitidine was given concomitantly. In general, ranitidine-induced changes in the in vivo absorption rate parameters for both dosage forms were opposite to those predicted from the in vitro dissolution rates. The results of this study demonstrated that the extent of theophylline absorption from controlled-release dosage forms, in control dogs and dogs with ranitidine-induced achlorhydria, corresponds to the pH-dependent in vitro dissolution properties of the products.