ESTRAMUSTINE - HYDROLYSIS, SOLUBILIZATION, AND STABILIZATION IN AQUEOUS-SOLUTIONS

The stability of estramustine, estradiol 3-bis(2-chloroethyl)carbamate, in buffered aqueous solutions was investigated over the pH range 1.0-11.2. The hydrolytic rate was unaffected by pH up to pH approx. 10 but increased at higher pH values The suggested unimolecular hydrolysis mechanism of the pH-independent region of the pH-rate profile, involving acyl-oxygen cleavage, is supported by the activation parameters, the solvent isotope effect and other data obtained during this investigation. The main hydrolysis product was estradiol. The effect of six cyclodextrin (CD) derivatives on the aqueous solubility of estramustine was investigated. All the CDs increased the solubility, but hepatkis(2,6-di-O-methyl)-beta-cyclodextrin (DM-beta-CD) and a mixture of maltosyl- and dimaltosyl-beta-cyclodextrin (M/DM-beta-CD) had the greatest effects. In the plateau region of the pH-rate profile, the hydrolysis of estramustine was about 2-times slower in a 1% aqueous M/DM-beta-CD buffer solution than in a solution containing no CD.