Physicochemical characterization and in vitro dissolution behavior of nicardipine-cyclodextrins inclusion compounds.

摘要

Inclusion complexation between nicardipine hydrochloride (NC), a calcium-channel antagonist, and beta-cyclodextrin (beta-CD) or hydroxypropyl-beta-cyclodextrin (HPbetaCD) was evaluated in aqueous environment and in solid state. The phase solubility profiles with both cyclodextrins (CDs) were classified as A(L)-type, indicating the formation of 1:1 stoichiometric inclusion complexes. Stability constants (Ks) were calculated from the phase solubility diagrams and were found to be pH dependent. More stable NC:CDs complexes were formed in alkaline medium in which the drug is in its non-ionized form. Binary systems of NC with CDs, prepared experimentally by different techniques (kneading, evaporation, freeze-drying and spray-drying), were investigated by differential scanning calorimetry, Fourier transformation-infrared spectroscopy, X-ray diffractometry and scanning electron microscopy. From this analysis, evaporation, freeze-drying and spray-drying were found to produce inclusion complexes. In contrast, crystalline drug was still clearly detectable in the kneaded products. The dissolution profiles of the obtained powders were studied in order to define the most appropriate CD and preparation method to originate inclusion complexes, which will be used in the development of a new controlled release formulation of NC. Both the preparation and nature of carrier played an important role in the dissolution performance of the system. However, independently of the preparation technique, all the combinations with HPbetaCD were more effective in achieving the enhancement of the NC dissolution rate, yielding better performances than the corresponding ones with betaCD.