Solubility and intrinsic dissolution rate of alprazolam crystal modifications.

Abstract

The purpose of the study was to determine the solubility and the intrinsic rates of dissolution of three crystal modifications, two anhydrate, and one dihydrate of alprazolam, a 1,4-benzodiazepine derivative. Solubility was determined by ultraviolet spectrophotometry at different levels of pH, and intrinsic dissolution rates were determined by a rotating disk method. The apparent solubility of alprazolam crystal modifications was dependent on pH, being 8-10 mg/ml at pH 1.6 and 0.1 mg/ml at pH 5.0. The apparent solubility values for the anhydrate forms were similar, whereas the hydrate form showed lower apparent solubility at each pH. The mean intrinsic rates of dissolution for the anhydrate forms were 16 and 18 micrograms cm-2 min-1, and for the dihydrate modification 21 micrograms cm-2 min-1 at 50 rpm, respectively. At 75 rpm, the corresponding values were 22, 22, and 27 micrograms cm-2 min-1. The rate of intrinsic dissolution was also dependent on the pH. It can be concluded that the apparent solubility and the intrinsic dissolution rate of the anhydrate and hydrate forms were different. The obtained apparent solubility values at different levels of pH for the water-solvated crystal modification were evidently lower than those of the two anhydrate forms studied. Furthermore, the intrinsic rate of dissolution was significantly (p < 0.05) higher for the hydrate form of alprazolam.