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Polymorphic transition of carbamazepine during hot melt processing
* 1 , 1, 2 , 3 , 3 , 3 , 1 , 1
1  Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark
2  Département de pharmacie, Université de Liegé, Bât. B36 Chimie analytiqueavenue de l'Hôpital 1, 4000 Liège, Belgique
3  Egalet Ltd., Lejrvej 37-39, 3500 Værløse, Denmark

Abstract: The aim was to study how hot melt (HM) process parameters affect the formation of carbamazepine containing Egalet® tablets and their functionality. A fractional factorial 24 design of experiment (DoE) was composed, where the investigated factors were melting temperature (90, 115 and 140 °C), melting time (10, 25 and 40 min), drug loading (15, 30 and 50 % (w/w)) and molecular weight of the polymer (PEG 35 000, PEO 100 000 and 300 000). Hot melt processing was performed on injection molding system (HAAKE MiniJet, Thermo Scientific, Germany). Powder blend was placed into a barrel, heated into given temperature and for the time period described in the DoE, which after the molten mass was injected into a mould (height 6 mm, volume 50 mm3, 25 °C). The polymorphic form of API was determined using X-ray diffractometer (X\'Pert Powder, Pan Analytical, The Netherlands, a continuous 2θ scan, range of 2 to 40°, step size 0.0263 °2θ, scanspeed of 0.0673 °2θ/s). In vitro release behaviour of the Egalet® tablets were determined by paddle method (Vankel VK 7025 Dissolution tester, Agilent Technologies, USA, 900ml, 50 rpm, 37 °C, pH 1.2) using a wavelength of 269 nm (Cary UV-Vis specthrometer, Agilent Technologies, USA). The results indicate that the HM process can induce polymorphic transition of API and the most crucial process parameters are melting temperature and molecular weight of the polymer. High process temperature and low molecular weight of the polymer induced polymorphic transition of API, which might be due to the dissolution of the API into rapidly melting polymer during the process and consequent recrystallization of API into metastable polymorphic form after the molten mass was injection molded and cooled down. Furthermore, the results indicate that the polymorphic transition can affect the release rate of the API.
Keywords: hot melt process, process parameters, carbamazepine, polymorph, release rate