Preformulation study of the inclusion complex warfarin-beta-cyclodextrin.
Inclusion complex between warfarin and beta-cyclodextrin was obtained to improve the in vitro bioavailability of the drug in acidic media. Inclusion complexation in solution was studied by phase solubility technique. The apparent stability constant was influenced by the pH of the medium ranging from 633.26 M(-1) (at pH 1.2, where the drug was in unionised form) to 99.81 M(-1) (at pH 7.4, where the drug was in ionised form). Phase solubility study showed an AL-type diagram indicating the formation of an inclusion complex in 1:1 molar ratio. Solid binary mixtures of the drug with beta-cyclodextrin were prepared by several methods (physical mixing, kneading, co-evaporation, freeze-drying). Physicochemical characterizations were performed using differential scanning calorimetry, powder X-ray diffractometry and dissolution studies. Preparation method influenced the physicochemical properties of the binary mixtures. An inclusion complex was obtained by freeze-drying, and it showed a high solubility and drug dissolution rate. The physical stability of the complex was also studied. After one year storage in glass container at room temperature no significant changes were detected in the diffractogram, thermogram and dissolution profile of the freeze-dried product.
Zingone
G
G
Department of Pharmaceutical Sciences, University of Trieste, Piazzale Europa 1, 34127 Trieste, Italy. zingone@units.it
Rubessa
F
F
D002152:Calorimetry, Differential Scanning / Q000379:methods; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D003505:Cyclodextrins / Q000032:analysis* / Q000737:chemistry; D004337:Drug Carriers / Q000032:analysis / Q000737:chemistry; D004355:Drug Stability; D005612:Freeze Drying / Q000379:methods; D006863:Hydrogen-Ion Concentration; D057927:Hydrophobic and Hydrophilic Interactions; D012995:Solubility; D013997:Time Factors; D014859:Warfarin / Q000032:analysis* / Q000737:chemistry; D014961:X-Ray Diffraction / Q000379:methods
D003505:Cyclodextrins; D004337:Drug Carriers; D014859:Warfarin