INCLUSION COMPLEXATION OF HEPTAKIS(2,6-DI-O-ETHYL)-BETA-CYCLODEXTRIN WITH TIAPROFENIC ACID - PHARMACOKINETIC CONSEQUENCES OF A PH-DEPENDENTRELEASE AND STEREOSELECTIVE DISSOLUTION

beta-Cyclodextrin was ethylated at the 2- and 6-hydroxyl positions. Di ethyl sulfate was employed as an alkylating reagent. NMR spectra data indicate that heptakis(2,6-di-O-ethyl)-beta-cyclodextrin (DCD) is the principal component of the product obtained. In addition, the FAB mass spectra obtained in nitrobenzyl alcohol and glycerin matrices gave ps eudo-molecular ions with mit ratios of 1630.75 and 1711.90 correspondi ng to C70H126O35[2Na . NaCl] and C70H126O35[2C(3)H(8)O(3)], respective ly, The dissolution of tiaprofenic acid (TA) enantiomers, from TA powd er (10 mg) and inclusion complex and/or coprecipitate (IC) (TA:DCD 1:1 molar ratio, equivalent to 10 mg of free TA), were examined using the dispersion method at pH values of 1.5, 3.0, and 7.4. Complex formatio n with the hydrophobic DCD resulted in a significant reduction in the release rate of both R- and STA, as compared to that observed with the powder. At pH 1.5, tiaprofenic acid enantiomers were not released fro m IC, compared to 20.52 +/- 1.47% of R-TA and 20.47 +/- 1.64% of S-TA dissolved from the powder. The greatest stereoselectivity in release p rofiles was found at pH 3.0 from IC [S:R 24 h cumulative percent relea se (Sigma R24) ratio of 0.88 +/- 0.04]. Elevation of the pH to 7.4, wh ich resulted in a faster dissolution and greater Sigma R24 of enantiom ers from both powder and IC, was accompanied by a parallel reduction i n the stereoselectivity. Following single 20 mg/kg oral doses of racem ic TA as both powder or IC to Sprague-Dawley rats, significant stereos electivity was observed in the plasma concentration profiles of the en antiomers (S:R AUC((0-infinity)) = 1.5), Despite significant reduction in the rate and extent of absorption, there was not a significant dif ference in the observed in vivo stereoselectivity between the two form ulations. Therefore, the in vivo importance of the observed stereosele ctivity in release at pH 3.0 is ruled out. Nevertheless, consideration must be given to the possibility of stereoselective release when chir al excipients are used in the formulation of racemic drugs.