Experimental and theoretical analysis of the interaction of (+/-)-cis-ketoconazole with beta-cyclodextrin in the presence of (+)-L-tartaric acid.
1H NMR spectroscopy was used for determining the optical purity of cis-ketoconazole enantiomers obtained by fractional crystallization. The chiral analysis was carried out using beta-cyclodextrin in the presence of (+)-L-tartaric acid. The mechanism of the chiral discrimination process, the stability of the complexes formed, and their structure in aqueous solution were also investigated by 1H and 13C chemical shift analysis, two-dimensional NOE experiments, relaxation time measurements, and mass spectrometry experiments. Theoretical models of the three-component interaction were built up on the basis of the available NMR data, by performing a conformational analysis on the relevant fragments on ketoconazole and docking studies on the components of the complex. The model derived from a folded conformation of ketoconazole turned out to be fully consistent with the molecular assembly found in aqueous solution, as inferred from NOE experiments. An explanation of the different association constants for the complexes of the two enantiomers is also provided on the basis of the interaction energies.
Redenti
E
E
Chemical and Biopharmaceutical Department, Chiesi Farmaceutici S.p.A., Via Palermo, 26/A, I-43100 Parma, Italy.
Ventura
P
P
Fronza
G
G
Selva
A
A
Rivara
S
S
Plazzi
P V
PV
Mor
M
M
D000935:Antifungal Agents / Q000737:chemistry* / Q000302:isolation & purification; D003505:Cyclodextrins / Q000737:chemistry*; D004347:Drug Interactions; D004355:Drug Stability; D007654:Ketoconazole / Q000737:chemistry* / Q000302:isolation & purification; D013058:Mass Spectrometry; D008958:Models, Molecular; D008968:Molecular Conformation; D019906:Nuclear Magnetic Resonance, Biomolecular; D011522:Protons; D012996:Solutions / Q000737:chemistry; D013237:Stereoisomerism; D013644:Tartrates / Q000737:chemistry*; D013816:Thermodynamics; D014867:Water / Q000737:chemistry; D047392:beta-Cyclodextrins
D000935:Antifungal Agents; D003505:Cyclodextrins; D011522:Protons; D012996:Solutions; D013644:Tartrates; D047392:beta-Cyclodextrins; D014867:Water; C031215:betadex; D007654:Ketoconazole; C029768:tartaric acid