Physicochemical properties and bioavailability of carbamazepine polymorphsand dihydrate

The dissolution behaviors of carbamazepine (CZP) polymorphs and pseudoporym orphs (form I, form III and dihydrate) and the bioavailabilities (BA) of ea ch form in dogs after oral administration were investigated. Bioavailabilit y tests were carried out at a dose of either 40 mg/body or 200 mg/body. The results of dissolution tests in JP13 first fluid (pH 1.2) at 37 degrees C indicated that the initial dissolution rate was in the order of form III > form I > dihydrate, while form III was transformed to dihydrate more rapidl y than form I, resulting in decrease of the dissolution rate. The solubilit ies of both anhydrates (form I and form III), calculated from the initial d issolution rate of each anhydrate, were 1.5-1.6 times that of the dihydrate . At the dose of 40 mg/body, there were no significant differences in the a rea under the curve (AUC) between forms; their AUCs were nearly equal to th at of CZP solution using polyethyleneglycol 400. These findings suggested t hat most crystalline powder of each form administered at the low dose was r apidly dissolved in gastrointestinal (GI) fluid. On the other hand, for the dose of 200 mg/body, significant differences in plasma concentration-time curves of CZP among polymorphic forms and dihydrate were observed. The orde r of AUC values was form I > form III > dihydrate. The inconsistency betwee n the order of initial dissolution rates and that of AUC values at the high dose may have been due to rapid transformation from form III to dihydrate in GI fluids. (C) 2000 Published by Elsevier Science B.V. All rights reserv ed.