EFFECT OF SBE4-BETA-CD, A SULFOBUTYL ETHER BETA-CYCLODEXTRIN, ON THE STABILITY AND SOLUBILITY OF O-6-BENZYLGUANINE (NSC-637037) IN AQUEOUS-SOLUTIONS

The effect of SBE4-beta-CD, a sulfobutyl ether derivative of beta-cyclodextrin on the solubility and aqueous hydrolysis of the antitumor drug O-6-benzylguanine (BG) was studied. SBE4-beta-CD is an apparently parenterally safe anionic p-cyclodextrin derivative with superior solubilizing properties in water. BG has poor aqueous solubility and undergoes rapid hydrolysis to the poorly water soluble guanine. The stability of a parenteral BG formulation was studied after storage at 25, 37 and 50 degrees C. Compared to the intrinsic solubility of BG (0.14 mg/ml, 25 degrees C), 0.05 M SBE4-beta-CD enhanced its solubility to 2.9 mg/ml at 25 degrees C and 3.9 mg/ml at 50 degrees C. Solubility data yielded binding constants (K-b) of 565 M(-1) at 25 degrees C and 342 M(-1) at 50 degrees C. The solubility of guanine was only slightly enhanced by SBE4-beta-CD. Hydrolysis kinetics of BG were studied at 50 degrees C over a pH range of 1-9 and the maximum stability was observed at pH 8-8.5. In the presence of 0.05 M SBE4-beta-CD, hydrolysis was about 9.5-times slower at pH 1, 14.6-times slower at pH 6 and 10-times slower at pH 8. The effect of SBE4-beta-CD concentration was studied at pH 2.2 and 4.8 at 50 degrees C. Hydrolysis rate constants decreased with increasing SBE4-beta-CD concentrations. A non-linear regression analysis of this data yielded K-b values of 311 and 270 M(-1) at pH 2.2 and 4.8, respectively. A formulation containing 2.5 mg/ml of BG and 0.05 M SBE4-beta-CD in a pH 8 phosphate buffer was stored in ampoules at 25, 37 and 50 degrees C. Guanine production in the samples was measured since its low solubility (2.5 mu g/ml) imposed a limitation on the shelf life. Guanine levels exceeded its apparent solubility after 1-2 months of storage at 50 degrees C. At 37 degrees C guanine levels were only 1.6 mu g/ml after 343 days of storage whereas those at 25 degrees C were negligible and below the limit of quantitation (approx. 0.1 mu g/ml). The greater stability at room temperature may be attributed to the higher K-b value observed and greater intrinsic stability of BG in the complex.