IMPROVEMENT OF SOME PHARMACEUTICAL PROPERTIES OF DRUGS BY CYCLODEXTRIN COMPLEXATION .5. THEOPHYLLINE

The interaction of theophylline (TPH) with beta-cyclodextrin (beta-CD) was investigated by spectrophotometry, vapour pressure osmometry and DSC. The results revealed a molecular interaction between TPH and beta -CD. The continuous variation method was used to elucidate the stoichi ometry of such an interaction by spectrophotometric as well as vapour pressure measurements. Both types of data revealed the formation of tw o-to-one TPH/beta-CD complex. The stability constant of the complex wa s determined at different temperatures by the vapour pressure osmometr ic method. The enthalpy and entropy of the interaction were evaluated and the results indicate the liberation of little heat during complexa tion and the disorder of the guest molecule upon complexation. The eff ect of beta-CD on the solubility of TPH indicates that beta-CD exhibit s a definite solubilizing effect towards the drug with a typical B-s i sotherm. The stability constant of the complex and the amount of drug solubilized in the form of complex reveal that complex-formation is th e only factor governing the solubilizing effect of beta-CD towards the drug. The dissolution rates of TPH, TPH/beta-CD physical mixture as w ell as the prepared complex were determined according to U.S.P. method and at pH 1.2. In both cases, the dissolution profile of the complex reveals enhanced dissolution properties compared to the drug. The effe ct of beta-CD on the partition properties of TPH reveals decrease in p resence of beta-CD. The effect of beta-CD on the bioavailability of TP H was investigated in human subjects. A clear difference in the biolog ical performance between the drug and the complex was revealed. The ph armacokinetic parameters including C-max t(max), C-min, t(1/2), K-e, M RT and AUC revealed that inclusion complexation of theophylline in B-c yclodextrin results in not only an improvement in the bioavailability of the drug, but also to acquired sustained release properties for the drug.