Quantitative Phase Analyses Through The Rietveld Method with X-Ray Powder Diffraction Data of Heat-Treated Carbamazepine Form III SELMA GUTIERREZ ANTONIO, 1 FERNANDA RIBEIRO BENINI, 1 FABIO FURLAN FERREIRA, 2 PAULO C ´ ESAR PIRES ROSA, 3 CARLOS DE OLIVEIRA PAIVA-SANTOS 1 1 Departamento de F´ ısico-Qu´ ımica, Instituto de Qu´ ımica, Universidade Estadual Paulista, Araraquara, Sao Paulo, Brazil 2 Centro de Ciˆ encias Naturais e Humanas, Universidade Federal do ABC, Rua Santa Ad´ elia, Santo Andr´ e, Sao Paulo, Brazil 3 Departamento de Qu´ ımica Anal´ ıtica, Instituto de Qu´ ımica, Universidade Estadual de Campinas, Campinas, Sao Paulo, Brazil Received 16 August 2010; revised 14 December 2010; accepted 14 December 2010 Published online 21 January 2011 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/jps.22482 ABSTRACT: The present work shows that the heated carbamazepine (CBZ) powder form III can be described as purely triclinic form I or a mixture of triclinic form I and monoclinic form III, depending on the resolution of the X-ray diffraction equipment used. Visual identification of the minor phase is possible when high-resolution synchrotron light is used. Quantitative phase analyses of CBZ forms I and III, after thermal treatment, were performed by using both syn- chrotron and conventional copper rotating anode X-ray powder diffraction data and the Rietveld method. Also, the Rietveld method could be adequately applied to determine the phase percent- age in the heated material, even when usual resolution data are acquired. © 2011 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:2658–2664, 2011 Keywords: X-ray powder diffractometry; polymorphism; crystallography; crystal structure; solid-state stability; quantitative phase analysis; synchrotron; carbamazepine; Rietveld method INTRODUCTION Carbamazepine (CBZ; Fig. 1), IUPAC name 5H- dibenz[b,f]azepine-5-carboxamide (C 15 H 12 N 2 O, M= 236.269 gmol −1 ), is used in the management of com- plex partial seizures, as an adjunct in some patients with secondary or partial epilepsy (epilepsy originat- ing in one area of the brain) with complex symp- tomatology, or secondarily generalized seizures (par- tial seizures followed by epileptic activity in the entire brain) when administered in combination with other antiepileptic drugs. 1 It has also been found useful as a mood-stabilizing drug to treat epilepsy and trigem- inal neuralgia. 2 As an oral preparation, CBZ has a well-established therapeutic profile with nearly 40 years of clinical use in the United States and around the world. 3 Concerning its crystal structures, CBZ crystallizes in four different anhydrous polymorphs. A complete Correspondence to: Selma Gutierrez Antonio (Tele- phone: +55-16-3301-6640; Fax: +55-16-3301-6692; E-mail: selma.antonio@gmail.com) Journal of Pharmaceutical Sciences, Vol. 100, 2658–2664 (2011) © 2011 Wiley-Liss, Inc. and the American Pharmacists Association list of references, with the different nomenclature of these four CBZ polymorphs, can be found in the work of Grzesiak et al. 4 Moreover, CBZ can form a dihydrate 5,6 and several cocrystals or molecular adducts. 7 The crystal structures of CBZ form III have been described as P-monoclinic. The Cambridge Structural Database provides for them two monoclinic crystal structures with space groups P2 1 /c 8 and P2 1 /n. 9 The P2 1 /n space group provides the same solution of P2 1 / c and does not represent another polymorph. 9 This form is considered to be the most stable, presenting higher solubility and bioavailability at room temper- ature of the known polymorphs. 10 Carbamazepine form I has been described as tri- clinic P ¯ 1, and it is an enantiotropic pair of form III at approximately 185 ◦ C. The demonstration of different structures by single-crystal X-ray diffraction is currently regarded as definitive evidence of polymorphism. However, X- ray powder diffraction can also be used to provide un- equivocal proof of polymorphism. 11,12 Among others, these are the prerequisite techniques for structural characterization of pharmaceutical polymorphs. 11 2658 JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 100, NO. 7, JULY 2011