Physicochemical properties and bioavailability of carbamazepine polymorphs and dihydrate.
The dissolution behaviors of carbamazepine (CZP) polymorphs and pseudopolymorphs (form I, form III and dihydrate) and the bioavailabilities (BA) of each form in dogs after oral administration were investigated. Bioavailability 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 rapidly than form I, resulting in decrease of the dissolution rate. The solubilities of both anhydrates (form I and form III), calculated from the initial dissolution 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 area under the curve (AUC) between forms; their AUCs were nearly equal to that of CZP solution using polyethyleneglycol 400. These findings suggested that most crystalline powder of each form administered at the low dose was rapidly 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 order of AUC values was form I>form III>dihydrate. The inconsistency between 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.
Kobayashi
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Y
Research Center, Taisho Pharmaceutical Company Ltd, 1-403 Yoshinocho, Omiya, Saitama, Japan.
Ito
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S
Itai
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S
Yamamoto
K
K
D000465:Algorithms; D018712:Analgesics, Non-Narcotic / Q000737:chemistry* / Q000493:pharmacokinetics*; D000818:Animals; D001682:Biological Availability; D002152:Calorimetry, Differential Scanning; D002220:Carbamazepine / Q000737:chemistry* / Q000493:pharmacokinetics*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D018360:Crystallography, X-Ray; D004285:Dogs; D006813:Humidity; D007536:Isomerism; D008297:Male; D012995:Solubility; D013818:Thermogravimetry
D018712:Analgesics, Non-Narcotic; D002220:Carbamazepine