Studies On Solubility Enhancement Of Naringenin By Inclusion Complex With Hydroxypropyl-β-cyclodextrin

Naringenin (2,3-dihydro-5,7-dihydroxy-2-(4-hydroxyphenyl)-4H-1-benzopyran-4-one; molecular mass 272.25 g·mol-1), a molecule belonging to the class of flavanones, is widely distributed in lemon, grapefruit, oranges. Recently, naringenin has been reported to possess various biomedical effects, such as antiatherogenic, anti-inflammatory, antioxidant, anticarcinogenic and anti-antherogenic activity. Unfortunately, the bioavailability of naringenin is limited by its poor solubility in water. Therefore it is important to find effective methods to improve the solubility and dissolution rate of naringenin.Cyclodextrins are macrocyclic oligosaccharides composed of six to eight D-glucopyranose units linked byα-(1-4) bonds and widely used to improve the solubility and dissolution of poorly water-soluble drugs. Its unique structure provides a molecule with an exterior hydrophilic surface and interior hydrophobic cavity. HP-β-CD combines a relatively high water solubility with a low toxicity and a satisfactory inclusion ability.In this paper, the inclusion complexes of poorly water-soluble drugs with HP-β-CD were investigated using naringenin as model drug.(1) The solubility of naringenin in methanol, ethanol, butan-1-ol, propanone, and water was measured from (288.2 to 323.2) K. The solubility of naringenin in selected solvents increased with an increase of temperature. The highest solubility value was observed in propanone for naringenin, whereas the lowest was observed in water. The experimental data were fitted with the modified Apelblat equation.(2) The inclusion complexes were prepared by solution-agitation method. The influencing factors of inclusion complex were investigated and the most important factors were identified. The preparation procedure was optimized by orthogonal design. The results showed that the best reaction conditions for naringenin/ HP-β-CD were:the volume ratio for ethanol and water was 2:1, inclusion time was 12 h, inclusion temperature was 60℃.(3) The phase solubility profiles of naringenin with HP-β-CD were investigated to determine the inclusion type and calculate the stability parameters. It was found that the inclusion type of naringenin with HP-β-CD was AL. Binary systems of naringenin with HP-β-CD were characterized by Differential scanning calorimetry(DSC), X-ray diffractometry(XRD), Fourier transformation-infrared spectroscopy(FTIR).'H Nuclear magnetic resonance spectroscopy (1H NMR) and 2 D ROESY were also used to obtain information about the mode of interaction. The results showed that naringenin was encapsulated within HP-β-CD cavity. The inclusion mode involves A-ring deeply inserting into the cavity and orientating the secondary hydroxyl group side while B-ring of naringenin projecting from the primary hydroxyl group side.(4) The dissolution profiles of the inclusion complexes were determined and compared with those of original naringenin and physical mixtures. The results showed that the dissolution rate of naringenin was obviously enhanced by the inclusion complex. The stability of inclusion complex was evaluated according to the appearance, content, moisture absorption for naringenin. The results showed that the inclusion complex was not stable in the high humidity suggesting the complex should be kept in the dry environment. The heat and light stability experiment suggested that the inclusion complex was relatively stable.