Evaluation of actarit/gamma-cyclodextrin complex prepared by different methods

摘要

This study used actarit (ACT), an antirheumatic drug, to examine the molecular interaction of ACT and gamma-CD in a solid state as a result of cogrinding or freeze-drying and it assessed the dissolution of ACT. Differential scanning calorimetry revealed that coground ACT and gamma-CD at molar ratios of 1:2 and 1:3 and freeze-dried ACT and gamma-CD at molar ratios of 1:1 and 1:2 lacked an endothermic peak due to melting of ACT crystals. Thus, coground ACT and gamma-CD at a molar ratio of 1:2 had molecular interaction, as did freeze-dried ACT and gamma-CD at a molar ratio of 1:1. Powder x-ray diffraction revealed that coground and humidified ACT and gamma-CD at a molar ratio of 1:2 produced a characteristic diffraction peak at 2 theta = 15.2 degrees and 16.5 degrees due to the cage structure of gamma-CD. In addition, freeze-dried ACT and gamma-CD at a molar ratio of 1:1 that had been humidified produced a diffraction peak at 2 theta = 6.0 degrees and 15.9 degrees characteristic of a hexagonal structure with head-to-head channels due to gamma-CD. Assessment of dissolution revealed that ground mixtures (GMs) and freeze-dried mixtures had improved dissolution of ACT compared to ACT, ground ACT alone, and physical mixtures. The mechanism for this is presumably the result of molecular interaction in a solid state or molecular interaction in an aqueous solution. H-1-H-1 NOESY NMR spectra suggested that in a GM of ACT and gamma-CD the benzene ring and methyl group of ACT partially enter the CD cavity. In addition, spectra for freeze-dried ACT and gamma-CD suggested that protons of the methylene group of ACT and the benzene ring of ACT partially enter the CD cavity. These findings indicate that ACT and gamma-CD inclusion complexes feature different forms of inclusion depending on how they are prepared, e.g., cogrinding or freeze-drying. Findings also indicated that selection of a method of preparation may play a major role in drug development.