Cocrystallization of carbamazepine with amides: Cocrystal and eutectic phases with improved dissolution

Abstract

Carbamazepine is an anticonvulsant drug which belongs to Biopharmaceutics Classification System (BCS) Class II drugs. In this work, attempts have been made to enhance the dissolution of carbamazepine (CBZ) in aqueous medium by attempting cocrystallization with the coformers such as para-hydroxybenzamide (PHBAD), salicylamide (SAL) and pyrazinamide (PRZ). Binary phase diagrams were constructed by conducting Differential Scanning Calorimetry (DSC) analysis for these CBZ-coformer pairs in order to determine the nature of the solid phase and cocrystal forming zone. CBZ formed a 1:1 cocrystal phase with PHBAD from the eutectic melts at a stoichiometric ratio of 1:1 and 1:2 whereas it formed eutectics with SAL as well as PRZ. Single crystals of CBZ-PHBAD (1:1) cocrystal phase were obtained by solvent evaporation of CBZ-PHBAD eutectic melts in Acetone-Toluene (1:1 vol ratio). Interestingly, recrystallization of eutectic melt of CBZ-PHBAD (1:1) in 1,4-Dioxane produced crystals of para-hydroxybenzamide monohydrate. Crystal structure analysis showed that CBZ-PHBAD (1:1) cocrystal and para-hydroxybenzamide monohydrate crystallized in monoclinic space groups namely P21/c and P21/n respectively. CBZ formed intermolecular interaction with two molecules of PHBAD via O-H…O hydrogen bonding and N-H...O intermolecular interaction which results into a cocrystal. Powder Dissolution (PD) studies were conducted for the CBZ-PHBAD (1:1) cocrystal, CBZ-SAL and CBZ-PRZ eutectic mixtures in Phosphate Buffer Saline (PBS) at 37 °C. Among the three carbamazepine solid forms, CBZ-PHBAD cocrystal exhibited 6.5 times higher dissolution than raw carbamazepine while the CBZ-SAL-SSG-XCBZ-0.5 eutectic and CBZ-PRZ-SSG-XCBZ-0.5 eutectic phases exhibited 2.62 and 3.05 times enhanced dissolution than raw carbamazepine.