Influence of Polymorphic Form, Morphology, and Excipient Interactions on the Dissolution of Carbamazepine Compacts FANG TIAN, 1 NIKLAS SANDLER, 1 JAAKKO AALTONEN, 2,3 CAROLIN LANG, 1 DOROTHY J. SAVILLE, 1 KEITH C. GORDON, 4 CLARE J. STRACHAN, 2,3 JUKKA RANTANEN, 5 THOMAS RADES 1 1 School of Pharmacy, University of Otago, P.O. Box 913, Dunedin, New Zealand 2 Division of Pharmaceutical Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland 3 Drug Discovery and Development Technology Centre (DDTC), University of Helsinki, Helsinki, Finland 4 Department of Chemistry, University of Otago, Dunedin, New Zealand 5 Department of Pharmaceutics and Analytical Chemistry, Danish University of Pharmaceutical Sciences, Copenhagen, Denmark Received 25 May 2006; revised 12 July 2006; accepted 26 July 2006 Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.20756 ABSTRACT: To gain a deeper understanding of the behavior of carbamazepine (CBZ) and CBZ dihydrate (DH) compacts during in vitro dissolution tests various factors were investigated: hydrate formation of CBZ, crystal morphology, surface area, and excipient influence. Dissolution tests were performed in three different dissolution media: distilled water, hydroxypropyl methylcellulose (HPMC), and polyethylene glycol (PEG) solutions. For the CBZ compacts, the dissolution rate of CBZ in water was fastest (0.338 mg L 1 min 1 ). With increasing ability of the excipients to inhibit the hydration of CBZ (PEG < HPMC), surprisingly the dissolution rate of CBZ compacts decreased: PEG solution (0.314 mg L 1 min 1 ) > HPMC solution (0.257 mg L 1 min 1 ). This implies that DH formation resulted in an apparent increase in the dissolution rate rather than slowing it down. For the DH compacts, the dissolution rate in water (0.055 mg L 1 min 1 ) was slower than that of PEG and HPMC solutions (0.174 and 0.178 mg L 1 min 1 , respectively). The contact angle measurements showed a significantly higher value in water (61.08) than in PEG and HPMC solutions (44.88 and 43.18, respectively). Although the dissolution of CBZ and DH compacts in various dissolution media are complex processes, the influence and relative importance of these factors were clearly detected providing better understanding of the dissolution behavior of the drug. ß 2006 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 96:584– 594, 2007 Keywords: carbamazepine; dissolution; hydrate formation; morphology; surface area; excipients interactions; wetting; scanning electron microscopy INTRODUCTION In vitro dissolution tests have been accepted as indispensable quality-control procedures for drugs with low aqueous solubility and whose absorption which is dissolution rate limited (class II drugs with respect to Biopharmaceutics Classi- fication System, BCS), since they may provide important information about the in vivo absorp- tion of pharmaceuticals. 1,2 Carbamazepine (CBZ), a widely used antiepileptic drug, is one example requiring in vitro dissolution testing of tablets to ensure good bioavailability, because CBZ is practically water insoluble, and absorption is dissolution rate limited. 3 CBZ also has several 584 JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 3, MARCH 2007 Correspondence to: Niklas Sandler (Telephone: þ44(0) 1625230078; Fax: þþ64 3 479 7034; E-mail: niklas.sandler@astrazeneca.com) Journal of Pharmaceutical Sciences, Vol. 96, 584–594 (2007) ß 2006 Wiley-Liss, Inc. and the American Pharmacists Association