Multimodal molecular encapsulation of nicardipine hydrochloride by beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin and triacetyl-beta-cyclodextrin in solution. Structural studies by 1H NMR and ROESY experiments.

Proton nuclear magnetic resonance spectroscopy (1H NMR), which has become an important tool for in vitro study of cyclodextrin (CD) complexes, was used to study and structurally characterize the inclusion compounds formed in solution between nicardipine hydrochloride (NC) and beta-cyclodextrin (betaCD), hydroxypropyl-beta-cyclodextrin (HPbetaCD) and triacetyl-beta-cyclodextrin (TAbetaCD). The large variation of chemical shifts from protons located around the interior of the hydrophobic cavity (i.e. H-3, H-5 and H-6) coupled with minimal variation of shifts from protons located on the outer sphere of the betaCD (i.e. H-1, H-2 and H-4) provided clear evidence of inclusion complexation. In the presence of the different CDs, the aromatic protons of NC were the most affected, suggesting a strong involvement of the phenyl groups in the inclusion mechanism. The application of continuous variation method indicated the presence of complexes with a 1:1 host/guest stoichiometry for all the studied CDs. Two-dimensional rotating frame nuclear Overhauser effect spectroscopy (ROESY) experiments were carried out to further support the proposed inclusion mode. Inspection of the ROESY spectra allowed the establishment of spatial proximities between several aromatic hydrogens of the guest and the CD protons, indicating that the inclusion occurs by accommodation of the two aromatic groups of NC. All the experimental data were further rationalized to elaborate possible three-dimensional geometric models of inclusion complexes. From the aforementioned observations, we concluded there is no preference for inclusion of a particular aromatic ring. Instead, two types of 1:1 complexes with different inclusion structures may exist simultaneously in solution, being alternatively included through the wider side of the cavity, i.e. the so-called multimodal inclusion occurs in the interaction of NC with the different CDs.

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

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.