Study on the Inclusion Complexes of Bromazepam with Beta- and Beta-hydroxypropyl-cyclodextrins

Solubility enhancement of the water insoluble bromazepam was studied during the formation of its inclusion complexes with beta-cyclodextrin (beta-CD) and beta-hydroxypropyl-cyclodextrin (beta-HP-CD). The phase solubility technique established by Higuchi and Connors and UV-spectrophotometric methods (zero- and second-order derivative approaches) were used to measure the changes introduced in this chemical system. The amount of time, which was necessary to reach equilibrium between inclusion complexes and their free components, was estimated and found equal to 24 h. The study was carried out at (i) pH 7.0 and 25 degrees C and (ii) pH 7.4 and 37 degrees C. The solubility of bromazepam increased linearly as a function of concentration for both beta-and beta-hydroxypropyl-cyclodextrins. Thus, the phase solubility diagrams were classified as of A(L) type in all cases. Under the above-mentioned conditions, the formation constants of the inclusion complexes were calculated and their stoichiometry was evaluated, found in the range of 69-85 M(-1) and 1:1, respectively.