Analysis of the phase solubility diagram of a phenacetin/competitor/β-cyclodextrin ternary system, involving competitive inclusion complexation.

Ono, Naomi; Hirayama, Fumitoshi; Arima, Hidetoshi; Uekama, Kaneto.

Faculty of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.

Abstract

The competitive inclusion complexations in the ternary phenacetin/competitors/β-cyclodextrin (β-CyD) systems were investigated by the soly. method, where m-bromobenzoic acid (m-BBA) and o-toluic acid (o-TA) were used as competitors. The soly. changes of the drug and competitors as a function of β-CyD concn. in the ternary systems were formulated using their stability consts. and intrinsic solubilities. The decrease in soly. of phenacetin by the addn. of competitors could be quant. simulated by the formulation, when both drug and competitor give AL type soly. diagrams. On the other hand, when one of the guests gives a BS type soly. diagram, its soly. change was clearly reflected in that of the another guest, i.e., phenacetin gave an AL type soly. diagram in the binary phenacetin/β-CyD system and o-TA gave a BS type diagram in the binary o-TA/β-CyD system, but in the ternary phenacetin/o-TA/β-CyD system, a new plateau region appeared in the original AL type diagram of phenacetin. This was explained by the solubilization theory of Higuchi and Connors. The soly. anal. of the ternary drug/competitor/CyD systems may be particularly useful for detn. of the stability const. of a drug whose physicochem. and spectroscopic analyses are difficult, because they can be calcd. by monitoring the soly. change of a competitor, without monitoring that of a drug. Furthermore, the present results suggest that attention should be paid to the type of the phase soly. diagram, as well as the magnitude of the stability const. and the soly. of the complex, for a rational formulation design of CyD complexes.