Solid-state characterization and in vitro dissolution behavior of lorazepam: Hydroxypropyl-β-cyclodextrin inclusion...

The objectives of this research were to prepare and characterize inclusion complexes of lorazepam with hydroxypropyl-β-cyclodextrin and to study the effect of complexation on the dissolution rate of lorazepam, a water-insoluble drug. The phase solubility profile of lorazepam with hydroxypropyl-β-cyclodextrin was an AP-type, indicating the　formation of 2:1 stoichiometric inclusion complexes. Gibbs free energy values were all negative, indicating the spontaneous nature of lorazepam solubilization, and they decreased with an increase in the cyclodextrin concentration, demonstrating that the reaction conditions became more favorable as the concentration of cyclodextrins increased. Complexes of lorazepam were prepared with cyclodextrin using various methods such as physical mixing, kneading, spray-drying, and lyophilization. The complexes were characterized by differential scanning calorimetry, Fourier-transform infrared, scanning electron microscopy, and powder X-ray diffraction studies. These studies indicated that a complex prepared by lyophilization had successful inclusion of the lorazepam molecule into the cyclodextrin cavity. Complexation resulted in a marked improvement in the solubility and wettability of lorazepam. Among all the samples, a complex prepared with hydroxypropyl-β-cyclodextrin by lyophilization had the greatest improvement in the in vitro rate of lorazepam dissolution. The mean dissolution time for lorazepam decreased significantly after preparing complexes and physical mixtures of lorazepam with cyclodextrin. The similarity factor indicated a significant difference between the release profiles of lorazepam from complexes and physical mixtures and from plain lorazepam. Tablets containing complexes prepared with cyclodextrins had significant improvement in the release profile of lorazepam as compared to tablets containing lorazepam without cyclodextrin.