Influence of beta-cyclodextrin on the phase transition in carbamazepine polymorphs

Introduction

Carbamazepin (CBZ), a widespread used antiepileptic drug, branded as Tegretol, firstly was launched in form of Active Pharmaceutical Ingredient (API) as a commercially available polymorphic form III. Additionally, crystallographic studies on crystal packing motifs of carbamazepine molecules in crystal lattices, reveal that, a part of the firstly confirmed structure of polymorphic form III, this drug exists in three other polymorphic forms I, II and IV, as well as pseudopolymorph, dihyrdate form. (Grzesiak et al., 2003). Further solid-state testing confirmed that in terms of thermodynamical stability CBZ III and I are related as enantiotropic pair, former exerting higher stability at ambient temperatures, up to phase transition temperature (Tt≈71℃) when it is transformed in the later with melting temperature at 193 ℃. Due to the polarity of the CBZ molecule that is carbamylated derivative of iminostilbene, consequently that determine its lipophilicity, CBZ belongs to BCS class II of low water solubility and high permeability drug.

Compromising the differences in crystal packing between CBZ polymorphs III and I that exert differences in density and solubility with the requirements for sufficient plasma concentration available for favorable crossing the blood-brain barrier (BBB) and reaching receptor sites, remain the challenge for crystal engineering CBZ polymorphs with functional excipients which, based on their molecular structures, are appropriate for formation either of inclusion complexes (IC) or co-crystals (CC). In terms of processing the CBZ polymorph, either with solvents or by mechanochemical treatments, both technologies impose phase transition; the first one causes transformation of anhydrous polymorphs to CBZ dihydrate, and second lead to interconversion of stable to metastable forms by thermomechanical activation on crystal particle surface (Li et al., 2000). The outlined research objectives address the testing of the influence of beta cyclodextrin (BCD), native cyclic oligosaccharide, on controlling the phase transition of CBZ form III to form I, respectively toward the formation of inclusion complex by non-covalent interactions between nonpolar part of CBZ molecule and hydrophobic CBD cavity that interact each other in stoichiometric ratio.

Мaterials and methods

CBZ form III was prepared by recrystallization of the commercially available CBZ in methanol. CBZ form I was made by heating of column packed with powder of CBZ III at 180 ℃ for 10 min. Beta cyclodextrin, BCD ((Kleptose®) with 13 ±1.5 m/m crystalized water content was gifted by Roquette Fröres (FR). Binary solid samples CBZ III and CBZ I with BCD, respectively in molar ratio 1/1 were processed both by grinding and kneading. Grinding method was performed manually by grounding the mixtures during the 30 min in mortar with pestle, while for manual kneading 50 % V/V water ethanol solution was used for wetting and kneading the powders during the 30 min, then leaving to dry on ambient temperature. The CBZ pseudopolymorph, dihydrate form was prepared by slurry method, steering overnight the powder of CBZ form III in purified water, followed by filtering and drying the sediment. Differential Scanning Calorimetry (DSC) was used for monitoring the thermal profiles of the samples, while modified USP Dissolution apparatus 1 with ring for controlling surface area for dissolution, in order to minimize the effect of particle size and habits, was utilized for measuring Intrinsic Dissolution Rate (IDR).

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Aleksandar Cvetkovski, Elena Drakalska, Influence of beta-cyclodextrin on the phase transition in carbamazepine polymorphs, Macedonian pharmaceutical bulletin, 69 (Suppl 1) 189 – 190 (2023), Online ISSN,
DOI: 10.33320/maced.pharm.bull.2023.69.03.093