Abstract:
Ketoconazole (KZ), an imidazole antifungal, was formulated into inclusion complexes
via coprecipitation and kneading with β-cyclodextrin
(β-CD) as a carrier in 1:1 and 1:2 drug to carrier
ratios. The KZ-β-CD solid complexes were
characterized by X-ray diffraction and differential
scanning calorimetry (DSC). The diffraction pattern
of the pure drug revealed the drug to be highly
crystalline in nature, as indicated by numerous
distinctive peaks. The lack of numerous distinctive
peaks of the drug in KZ-β-CD complexes prepared
by the two methods revealed that a large number
of the drug molecules were dissolved in a solid-state
carrier matrix with an amorphous structure. The
thermograms of the KZ-β-CD complexes showed
a strong reduction in the intensity and broadening
of drug peaks somewhat in both kneading and
coprecipitation systems, suggesting that the drug
is monomolecularly dispersed in the β-CD cavity.
The prepared tablets of KZ-β-CD solid complexes
prepared by the two methods were evaluated for
their quality control testing, and an in vitro release
study and the results of quality control complied with
pharmacopeial requirements and the release profiles
indicated complete drug release after 30 min. The
kinetic parameters obtained from release data were
analyzed in order to explain the mechanism of
drug release and revealed non-Fickian transport.
Accelerated stability testing at 35°C, 45°C, and 55°
C and at 75% relative humidity was carried out for
six months and revealed somewhat stable systems as
indicated by a t90 of about 2 years for both KZ-β-CD
systems. A microbiological in vitro assay of KZ from
the prepared tablets was performed using Candida
albicans as a model fungus, and KZ had improved
microbiological activity when administered as an
inclusion complex with β-CD. The results confirmed
the benefit of using CDs as a useful tool to enhance
the dissolution and hence bioavailability of poorly
water-soluble drugs by forming solubilizing systems
when exposed to gastrointestinal fluid.
