Stabilization mechanism of amorphous carbamazepine by transglycosylated rutin, a non-polymeric amorphous additive with a high glass transition temperature

Abstract

α-Glycosyl rutin (Rutin-G), composed of a flavonol skeleton and sugar groups, is a promising non-polymeric additive for stabilizing amorphous drug formulations. In this study, the mechanism of the stabilization of the amorphous state of carbamazepine (CBZ) by Rutin-G was investigated. In comparison with hypromellose (HPMC), which is commonly used as a crystallization inhibitor for amorphous drugs, Rutin-G significantly stabilized amorphous CBZ. Moreover, the dissolution rate and the resultant supersaturation level of CBZ were significantly improved in the CBZ/Rutin-G spray-dried samples (SPDs) owing to the rapid dissolution property of Rutin-G. Differential scanning calorimetry measurement demonstrated a high glass transition temperature (Tg) of 186.4°C corresponding to Rutin-G. The CBZ/Rutin-G SPDs with CBZ weight ratios up to 80% showed single glass transitions, indicating the homogeneity of CBZ and Rutin-G. A solid-state NMR experiment using 13C- and 15N-labeled CBZ demonstrated the interaction between the flavonol skeleton of Rutin-G and the amide group of CBZ. A 1H-13C two-dimensional heteronuclear correlation NMR experiment and quantum mechanical calculations confirmed the presence of a possible hydrogen bond between the amino proton in CBZ and the carbonyl oxygen in the flavonol skeleton of Rutin-G. This specific hydrogen bond could contribute to the strong interaction between CBZ and Rutin-G, resulting in the high stability of amorphous CBZ in the CBZ/Rutin-G SPD. Hence, Rutin-G, a non-polymeric amorphous additive with high Tg, high miscibility with drugs, and rapid and pH-independent dissolution properties could be useful in the preparation of amorphous formulations.