The physicochemical characteristics and bioavailability of indomethacin from beta-cyclodextrin, hydroxyethyl-beta-cyclodextrin, and hydroxypropyl-beta-cyclodextrin complexes.
In an effort to improve the bioavailability of the insoluble drug indomethacin, three complexes were prepared with indomethacin and the soluble complexing agents beta-, hydroxyethyl-beta-, and hydroxypropyl-beta-cyclodextrin. The indomethacin content was similar among the complexes (P</=0.05). To confirm complex formation, each complex was characterized by ultraviolet, infrared, nuclear-magnetic resonance, powder X-ray diffraction, and differential-scanning calorimetry techniques. Powder diffraction studies show the beta-cyclodextrin complex was polycrystalline, and the hydroxyethyl- and hydroxypropyl-beta-cyclodextrin complexes were amorphous. Phase-solubility analysis confirmed the formation of complexes and suggested the three complexes were bound similarly. Solubility studies show complexation increased indomethacin solubility, and the hydroxyethyl- and hydroxypropyl-beta-cyclodextrin complexes were more soluble than the beta-cyclodextrin complex in 0.1 N hydrochloric acid and distilled water. Dosage forms were prepared by encapsulating the complexes without the addition of excipients. Dissolution studies show the encapsulated beta- and hydroxyethyl-beta-cyclodextrin complexes had superior dissolution when compared to the hydroxypropyl-beta-cyclodextrin and Indocin (50 mg) capsules. Bioavailability studies were performed by administering the indomethacin complex or Indocin capsules to male-albino, New Zealand rabbits. Indomethacin plasma-time concentration data fit best to a compartment-independent model for all capsule formulations. Bioavailability comparisons by ANOVA show no significant difference (P</=0.10) in the peak-plasma time and peak concentration among the capsule formulations. The area-under-the-curve for the beta-cyclodextrin complex capsules was found to be significantly higher (P</=0.10) than all other capsule formulations. In conclusion, the bioavailabilty of indomethacin was improved by complexation with only beta-cyclodextrin. No correlations were found among the bioavailability, solubility, and dissolution results.
Jambhekar
Sunil
S
Department of Pharmaceutical Sciences, Massachusetts College of Pharmacy and Health Sciences, 179 Longwood Avenue, Boston, MA 02115, USA.
Casella
R
R
Maher
T
T
D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000284:Administration, Oral; D000641:Ammonia / Q000737:chemistry; D000818:Animals; D001682:Biological Availability; D002152:Calorimetry, Differential Scanning; D002214:Capsules; D002851:Chromatography, High Pressure Liquid; D003460:Crystallization; D003505:Cyclodextrins / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D007213:Indomethacin / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D011817:Rabbits; D012995:Solubility; D013055:Spectrophotometry, Infrared; D014867:Water / Q000032:analysis; D014961:X-Ray Diffraction; D047392:beta-Cyclodextrins
D002214:Capsules; D003505:Cyclodextrins; D047392:beta-Cyclodextrins; D014867:Water; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000641:Ammonia; C059250:2-hydroxyethyl-beta-cyclodextrin; C031215:betadex; D007213:Indomethacin