Inclusion complexation of heptakis(2,6-di-O-ethyl)-beta-cyclodextrin with tiaprofenic acid: pharmacokinetic consequences of a pH-dependent release and stereoselective dissolution.
beta-Cyclodextrin was ethylated at the 2- and 6-hydroxyl positions. Diethyl 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 pseudo-molecular ions with m/z ratios of 1630.75 and 1711.90 corresponding to C70H126O35[2Na.NaCl] and C70H126O35[2C3H8O3], respectively. The dissolution of tiaprofenic acid (TA) enantiomers, from TA powder (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 formation with the hydrophobic DCD resulted in a significant reduction in the release rate of both R- and S-TA, as compared to that observed with the powder. At pH 1.5, tiaprofenic acid enantiomers were not released from 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 profiles was found at pH 3.0 from IC [S:R 24 h cumulative percent release (sigma R24) ratio of 0.88 +/- 0.04]. Elevation of the pH to 7.4, which resulted in a faster dissolution and greater sigma R24 of enantiomers from both powder and IC, was accompanied by a parallel reduction in the stereoselectivity. Following single 20 mg/kg oral doses of racemic TA as both powder or IC to Sprague-Dawley rats, significant stereoselectivity was observed in the plasma concentration profiles of the enantiomers (S:R AUC(0-infinity) = 1.5). Despite significant reduction in the rate and extent of absorption, there was not a significant difference in the observed in vivo stereoselectivity between the two formulations. Therefore the in vivo importance of the observed stereoselectivity in release at pH 3.0 is ruled out. Nevertheless, consideration must be given to the possibility of stereoselective release when chiral excipients are used in the formulation of racemic drugs.
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry* / Q000493:pharmacokinetics*; D003505:Cyclodextrins / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D011208:Powders; D011422:Propionates / Q000737:chemistry* / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D016339:Spectrometry, Mass, Fast Atom Bombardment; D013237:Stereoisomerism; D047392:beta-Cyclodextrins
D000894:Anti-Inflammatory Agents, Non-Steroidal; D003505:Cyclodextrins; D011208:Powders; D011422:Propionates; D047392:beta-Cyclodextrins; C021270:tiaprofenic acid; C038119:heptakis(2,6-O-dimethyl)beta-cyclodextrin