PRELIMINARY TOXICOKINETIC STUDY WITH DIFFERENT CRYSTAL FORMS OF S(-IBUPROFEN (DEXIBUPROFEN) AND R,S-IBUPROFEN IN RATS())

The aim of the study was to gain information on the plasma concentrati on-time profiles of both ibuprofen (CAS 15687-27-1) enantiomers in the rat after single oral application of two different crystal forms of S (+)-ibuprofen (dexibrufen, CAS 51146-56-6) and racemic ibuprofen in o rder to optimize blood-sampling times in a subsequent subchronic toxic ity study. The application of either commercial racemic ibuprofen or r ecrystallised S (+)-ibuprofen (60 mg/kg) to two groups of 4 rats per b lood sampling term was carried out in order to define C-max and t(max) and AUC of the plasma-concentrations of the ibuprofen enantiomers. Th e crystals of commercial (manufactured according to an usual manufactu ring procedure) and recrystallised (S(+)- and racemic ibuprofen were d ifferent in respect to their shape and size. The recrystallised crysta l species of S (+)- and racemic ibuprofen has better galenic (tabletti ng-) properties and tablets containing the modified S (+)-ibuprofen sp ecies showed favorable clinical results. The toxicokinetic behaviour o f the recrystallised species was investigated in comparison to the com mercial crystal species because of its slightly but significantly slow er dissolution rate in simulated gastric and enteric juice. As the AUC (0-24 h S-(+)-ibuprofen and the AUC(0-24 h R-(-)-ibruprofen) after app lication of commercial and recrystallised crystal species were not dif ferent, the crystal from apparently did not exert an influence on the extent of absorption of S-(+)-ibuprofen and racemic ibuprofen in the r at. The rat has a high inversion capacity and the inversion of R-(-)-i buprofen after application of commercial and recrystallised racemic ib uprofen was nearly complete in this study. The effects of crystallinit y on solubility in simulated media in vitro did not correlate to the f indings on the extent of absorption in the rat in vivo.